Blockbuster Cancer Treatment Using Ivermectin Plus High Dose Vitamin C, D and Zinc

by Dr. Clark Hansen, NMD | Oct 31, 2024

Targeting the Mitochondrial-Stem Cell Connection in Cancer Treatment: A Hybrid Orthomolecular Protocol

Ilyes Baghli¹, William Makis², Paul E. Marik³, Michael J. Gonzalez^4,5,6, William B. Grant⁷, Ron Hunninghake⁸, Thomas E. Levy⁸, Homer Lim⁹, Richard Z. Cheng¹⁰, Igor Bondarenko¹¹, Paul Bousquet¹², Roberto Ortiz¹³, Mignonne Mary¹⁴, Dominic P. D’Agostino¹⁵, Pierrick Martinez¹⁶

¹International Society for Orthomolecular Medicine, Toronto, ON, Canada
²Alberta Health Services, Cross Cancer Institute, Edmonton, AB, Canada
³Frontline COVID-19 Critical Care Alliance, Washington, DC, USA
⁴University of Puerto Rico, Medical Sciences Campus, School of Public Health, San Juan, PR
⁵Universidad Central del Caribe, School of Chiropractic, Bayamon, Puerto Rico
⁶EDP University, Naturopathic Sciences Program, Hato Rey, Puerto Rico
⁷Sunlight, Nutrition, and Health Research Center, San Francisco, CA, USA
⁸Riordan Clinic, 3100 North Hillside, Wichita, KS, USA
⁹Akesis Holistic Health, Manila, Philippines
¹⁰Cheng Integrative Health Center, Doctor’s Weight Loss Center, Columbia SC, USA
¹¹Medical Institute for Nutrition Science and Technology, Riga, LV-1005, Latvia.
¹²Association Internationale pour une Médecine Scientifique Indépendante et Bienveillante, Amiens, France
¹³ Mexican Association of Orthomolecular Nutrition, Mexico City, Mexico
¹⁴Remedy Room Integrative Medicine, New Orleans LA, USA
¹⁵Department of Molecular Pharmacology and Physiology, Laboratory of Metabolic Medicine, Morsani College of Medicine, University of South Florida, Tampa, FL, USA
¹⁶Association Cancer et Métabolisme, 30000 Nîmes, France.
Correspondence: [email protected](s): Baghli I, et al.

Date of Publication: 19 September 2024

Citation: Baghli I, et al. (2024) Targeting the Mitochondrial-Stem Cell Connection in Cancer Treatment: A Hybrid Orthomolecular Protocol. J Orthomol Med. 39.3

Article PDF

Links:

Vitamin C Cancer Protocol

Vitamin D Cancer Protocol

Zinc Cancer Protocol

Ivermectin Cancer Protocol

Abstract

The mitochondrial-stem cell connection (MSCC) theory suggests that cancer originates from chronic oxidative phosphorylation (OxPhos) insufficiency in stem cells. This OxPhos insufficiency leads to the formation of cancer stem cells (CSCs) and abnormal energy metabolism, ultimately resulting in malignancy. This concept integrates two well-established theories: the cancer stem cell theory and the metabolic theory. Drawing on insights from molecular biology, pharmacology, and clinical studies, this manuscript introduces a hybrid orthomolecular protocol targeting the MSCC. The protocol includes 7 therapeutic recommendations, consisting of orthomolecules, drugs, and additional therapies. The aim of this hybrid orthomolecular protocol is to achieve additive and synergistic effects to enhance OxPhos, inhibit the primary fuels of cancer cells (glucose and glutamine), target CSCs and metastasis. Thus, numerous experiments suggest that targeting MSCC could be a potential therapeutic approach for cancer treatment.

Keywords: cancer metabolism; mitochondria; oxidative phosphorylation; cancer stem cells; glucose; glutamine; orthomolecules; repurposed drugs; diet; lifestyle interventions

.
Introduction

Many theories exist regarding the origin of cancer, namely the metabolic theory (Seyfried & Chinopoulos, 2021), the somatic mutation theory (SMT) (Hanahan & Weinberg, 2000), the cancer stem cell theory (Capp, 2019), and the tissue organization theory (Soto & Sonnenschein, 2011). In a recently published study, a new concept was introduced the mitochondrial-stem cell connection (MSCC) (Martinez, et al., 2024). This concept combines the cancer stem cell theory and the metabolic theory. The MSCC theory suggests that cancer arises from impaired oxidative phosphorylation (OxPhos) in one or more stem cells, potentially leading to the formation of cancer stem cells (CSCs) and, consequently, tumorigenesis. This connection between CSCs and mitochondria appears to be crucial at all stages of cancer (Martinez, et al., 2024). The MSCC aligns with the metabolic theory of cancer but specifically focuses on the crucial role of CSCs in every stage of the disease. However, the MSCC differs from the CSCs theory, which typically presents cancer as a genetic disease. Thus, many standard cancer therapies are based on the SMT and generally target the DNA of cancer cells (van den Boogaard, et al., 2022; Sia, et al., 2020). These therapies do not restore OxPhos and sometimes even alter it (Averbeck & Rodriguez-Lafrasse, 2021; Gorini, et al., 2018). Furthermore, standard therapies only target bulk cells but cannot target CSCs (Lytle, et al., 2018), whereas it is CSCs that have the strongest tumorigenic potential (Adams & Strasser, 2008) and are involved in metastasis. This information could partially explain the outcomes observed with the new anticancer therapies. Indeed, Ladanie et al. showed that over the past fifteen years, new therapies have led to an overall survival improvement of 2.4 months (Ladanie, et al., 2020), while Del Paggio et al. reported an improvement of 3.4 months over the past thirty years (Del Paggio, et al., 2021).

Thus, after reviewing the literature on various therapies capable of targeting the MSCC, we selected, based on in vitro and in vivo studies, several orthomolecules, drugs, and additional therapies that have demonstrated an ability to enhance OxPhos, reduce fermentable fuels, and target CSCs and metastasis. Furthermore, when supported by scientific literature, we included case studies of cures using monotherapy in humans. From this combination, we developed a hybrid orthomolecular protocol, which is proposed as a new therapeutic strategy for cancer.

Key Points of the MSCC:

An alteration of OxPhos may initiate tumorigenesis in one or more normal stem cells, leading to the formation of CSCs (Martinez, et al., 2024).
The degree of malignancy could be directly correlated with significantly lower mitochondria and lower total respiratory capacity in tumor cells (Elliott, et al., 2012; Pedersen, 1978; Seyfried, et al. 2020).
In order to grow and survive, cancer cells require the primary fuels glucose and glutamine to compensate for OxPhos insufficiency. The respiratory impairment induces overexpression of oncogenes and inactivation of tumor-suppressor genes, which contribute to abnormal energy metabolism in cancer. To date, no evidence has demonstrated the growth of any tumor cells, including CSCs, occurs with the deprivation of fermentable fuels (glucose, pyruvate, or glutamine) (Lee, et al., 2024; Liao, et al., 2017; Holm, et al., 1995; Mathews, et al., 2014; Pastò, et al., 2014).
The tumor microenvironment (a consequence of mitochondrial impairment) is characterized by low pH (acidic), hypoxia, entropy, pressure and deformation, increased temperature, stroma, altered rotation of cytoplasmic water, and damped bioelectricity or electromagnetic field (Martinez, et al., 2024).
Metastasis remains the leading cause of cancer mortality. According to MSCC, it occurs due to fusion hybridization between CSCs and macrophages (Martinez, et al., 2024; Seyfried & Huysentruyt, 2013).

These principles are applicable to all types of cancer.

Orthomolecular Medicine for Targeting the MSCC

Vitamin C

The anti-cancer properties of vitamin C have been known for over 50 years (Mussa, et al., 2022). Vitamin C demonstrates cytotoxic effects on cancer cells both in vitro and in vivo (Fan, et al., 2023). In vitro, vitamin C alone is more effective than chemotherapy (cisplatin) alone at inducing apoptosis in colon cancer cells (Wang, et al., 2016). In vivo, vitamin C alone significantly reduces tumor weight and the number of metastases in pancreatic cancer, whereas standard chemotherapy (gemcitabine) alone, commonly used for pancreatic cancer, increases tumor weight and the number of metastases (Polireddy, et al., 2017). In vivo hepatocellular carcinoma, vitamin C alone reduces CSCs and tumor volume, whereas conventional therapy (cisplatin) alone reduces tumor volume (to a lesser extent than vitamin C) but increases CSCs (Lv, et al., 2018). Vitamin C can directly infiltrate into the tumor intracellular environment, reduce oxidative stress, target the mitochondria of cancer cells, and induce cancer cell death, including metastases (Roa, et al., 2020; Wan, et al., 2021). The alkaline intracellular environment of cancer cells, with a pH between 7.1 and 7.7, maximizes the proliferation of cancer cells (Cardone, et al., 2005; Gillies, et al., 2002). Vitamin C, through its acidic pH, could deactivate the environmental adaptations, having anti-cancer effects by compromising the growth of tumor cells and inhibiting tumor progression (Persi, et al., 2018). It can increase ATP production by increasing mitochondrial electron flux, thereby restoring cellular respiration and apoptosis function (Gonzalez, et al., 2010; Gonzalez, et al., 2023).

Vitamin C can target and eradicate CSCs (Bonuccelli, et al., 2017; Lee, 2023; Satheesh, et al., 2020), and protect against hypoxia and inflammation (Luo, et al., 2022). It can induce apoptosis in drug-resistant cancer cells, and inhibit uncontrolled proliferation of cancer cells and metastatic spread (Butt, et al., 2020). Vitamin C can also cause a polarization of M2 macrophages into M1 macrophages. This could be particularly relevant for inhibiting metastatic spread because M2 macrophages are implicated in metastases (Ma, et al., 2022). High pharmacological intravenous doses of vitamin C have been shown to kill cancer cells but not normal cells (Chen, et al., 2005; Chen, et al., 2008; Ngo, et al., 2019). For example, high doses of intravenous vitamin C may induce apoptotic cell death in tumor cell lines through a pro-oxidant mechanism (Gonzalez, et al., 2010; Kc, et al., 2005; Mussa, et al., 2022).

In normal cells, vitamin C enters mitochondria in its oxidized form via glucose receptors (Glut1) and protects mitochondria from oxidative injury (Kc, et al., 2005). Thus, vitamin C can directly compete with glucose for cellular entry by glucose receptor.

Glycolysis and glutaminolysis have a major role in the metabolism of cancer cells. Vitamin C has the ability to inhibit glycolysis (Aguilera, et al., 2016; Park, et al., 2018; Yu, et al., 2023) and glutamate synthesis (Zeng, et al., 2022). It can specifically limit glutamine synthesis by inhibiting glutamine synthetase (GS), leading to a decrease in the level of glutathione and an increase in reactive oxygen species (ROS) thus resulting in cell death (Long, et al., 2021). GS plays a key role in macrophages and thus in metastases. GS inhibition can reverse the phenotype of M2 macrophages and promote the polarization of M1 macrophages. It will reduce intracellular glutamine and the absorption of glutamine will be channeled, which will eliminate metastases (Wei, et al., 2020). Thus explaining the glutamine dependence observed in advanced cancers (Seyfried, et al., 2020) and confirming the role of vitamin C on metastatic cancers.

The pioneers of intravenous vitamin C cancer treatment, Cameron and Pauling, observed improved survival times for many cancers (lung, stomach, colon, breast, kidney, rectum, and bladder). They observed survival times multiplied by 55 after 1 year, in terminal cancer patients treated with intravenous injections of ascorbate: 22% in the treated group and 0.4% in the control group in patients considered to be incurable following standard treatment. Their intervention consisted of an intravenous injection of 10 g/day for approximately 10 days and orally thereafter (Cameron & Pauling, 1978). The Mayo Clinic attempted to reproduce these results, but intravenous vitamin C was replaced by oral vitamin C and the results were therefore unsurprisingly not reproduced (Moertel, et al., 1985). The plasma concentrations, and therefore the effects of vitamin C, are much lower with oral supplementation (Mikirova, 2017). Several case studies have been published by the Riordan Clinic team and collaborators, reporting cases of tumor regression in patients who received intravenous vitamin C (Riordan, et al., 2000; Riordan, et al., 2004; Sebastian, et al., 2006). Additionally, Li and colleagues showed that when taken regularly, antioxidant vitamins (vitamins A, C and E) could reduce cancer mortality (Li, et al., 2012). However, the antioxidant action of vitamin C should primarily be used in cancer prevention (Deruelle & Baron, 2008), as antioxidants can sometimes promote tumor growth (Long, et al., 2021).

Vitamin D

Vitamin D has shown anti-cancer effects in vitro and in vivo for almost all cancer types (Chakraborti, 2011; Seraphin, et al., 2023). Like vitamin C, it targets the mitochondria by improving metabolism and regulating mitochondrial respiration (Matta Reddy, et al., 2022; Quigley, et al., 2022). Vitamin D can also target CSCs and metastases (Marigoudar, et al., 2022; Wu, et al., 2019), and inhibit glycolysis and glutaminolysis pathways (Sheeley, et al., 2022; Zhou, et al., 2016). It has been observed that daily vitamin D supplementation can reduce total cancer mortality, but this has not been observed for infrequent large bolus doses (Keum, et al., 2022). Cancer patients are often deficient in vitamin D and they can benefit from effective therapy with minimal risk (Hohaus, et al., 2018), including intravenously (Dressler, et al., 1995; Fakih, et al., 2007; Trump, 2018). One case report details an elderly patient with advanced pancreatic cancer who was unable to undergo chemotherapy, radiation, or surgery. Instead, the patient received a daily dose of 50,000 IU of vitamin D3 for 9 months and experienced an unexpectedly prolonged period of disease-free progression, far exceeding what would have been expected with conventional chemotherapy (Cannon, et al., 2016).

Chandler et al. showed a preventive effect of vitamin D supplementation in patients with a normal body mass index (BMI), demonstrating a 37% reduction in the incidence of metastatic cancer (24 cancers in the vitamin D group and 39 cancers in the placebo group) leading to a reduction in cancer mortality of 42% (38 people in the Vitamin D group and 68 people in the placebo group). The dose utilized was 2000 IU/day, which is the recommended daily intake for a healthy individual (Chandler, et al., 2020). A recent randomized controlled trial on vitamin D supplementation (2000 IU/d vitamin D3 versus placebo) found that gastrointestinal cancer patients who were p53 immunoreactive experienced a significant reduction in relapse or death associated with vitamin D supplementation over nearly six years of follow-up (Kanno, et al., 2023). Meta-analyses of observational studies for at least 12 different cancer types reported the inverse correlations of serum 25-hydroxyvitamin D [25(OH)D] and cancer incidence (Muñoz & Grant, 2022).

Zinc

Zinc supplementation has been recommended as a possible adjunctive treatment for cancer. (Costello & Franklin, 2017; Hoppe, et al., 2021) Zinc specifically protects mitochondria from damage by reactive oxygen species that are generated as by-products of mitochondrial respiration (Zhang, et al., 2018). It has been shown that zinc supplementation induces mitochondrial pyruvate transport, oxidative phosphorylation, and ATP production in both normal and toxic-induced oxidative stress in vitro (Yang, et al., 2017). In human ovarian cancer cells, zinc induces degradation of mitochondria, and restores apoptosis, especially if introduced together with zinc ionophores (Chen, et al., 2020). Zinc can suppress cancer stem cell-like properties of oral cancer and breast cancer cells in vitro (Chu, et al., 2023; Xu, et al., 2022), reduce the expression of markers of cancer cell stemness, and enhance sensitivity to chemotherapy in colorectal cancer cells (Ye, et al., 2022). Excess zinc can irreversibly block energy production of cancer cells, cause NAD+ loss, and inhibit cellular glycolysis (Wu, et al., 2022).

There are a total of 151 publications confirming the link between zinc deficiency and malignancy (Sugimoto, et al., 2024). Zinc deficiency is implicated in many cancers, including oesophageal, liver, lung, breast, colon and others (Lu, et al., 2006; Tamai, et al., 2020; Wang, Y., et al., 2019; Wu, et al., 2015). Zinc shows toxicity toward cancer cells without showing any side effects toward healthy cells and deficiency negatively correlates with survival rates (Gelbard, 2022; Sugimoto, et al., 2024). Similar to vitamin C, zinc may have a specific pro-oxidant effect on cancer cells (Aljohar, et al., 2022).

Potential Drugs for Targeting the MSCC

Several pharmaceutical agents can primarily target genetic pathways associated with CSCs, including Vismodegib, Glasdegib, MK-0752, OMP-54F28, and Selinexor (Zhou, et al., 2021). Other pharmaceutical agents have been proposed to target mitochondria, such as Metformin for OxPhos (Ward, et al., 2017; Zheng, et al., 2023) Doxycycline, Tigecycline, and Bedaquiline for mitochondrial biogenesis; Mdivi-1 drug in mitochondrial dynamics; and 188Re-liposome and the inhibitor liensinine to block mitophagy (Jagust, et al., 2019; Praharaj, et al., 2022). Most of the time, these agents do not restore mitochondrial homeostasis (Liu, Y., et al., 2023), as their specific actions alter or only partly restore dysfunction. The alteration of mitochondrial function with pharmaceutical agents must be considered with caution, as it can be very dangerous for healthy cells (Vuda & Kamath, 2016).

Repurposed (off-label) Drugs for Targeting the MSCC

Ivermectin

An anti-parasitic derived from a bacteria called Streptomyces avermitilis, Ivermectin has anti-cancer properties and induces autophagy and apoptosis of cancer cells (Liu, et al., 2020). Ivermectin has shown a significant impact on various cancer cell lines (Juarez, et al., 2020), inducing apoptosis in cancer cells in vivo (Sharmeen, et al., 2010) and significantly reducing tumor volume compared to a control (Juarez, et al., 2020). It induces apoptosis in cancer cells through mitochondrial mediation (Juarez, et al., 2018; Tang, et al., 2021). Ivermectin can target and regulate the pyruvate kinase muscle isoforms at the last step of glycolysis (Li, et al., 2020). It can inhibit glycolysis inducing autophagy (Feng, et al., 2022), and have a selective pro-oxidant effect on cancer cells (Wang, et al., 2018). It can also target CSCs and metastases (Dominguez-Gomez, et al., 2018; Jiang, et al., 2022) and macrophages (Zhang, et al., 2022). In vitro, Ivermectin is more effective at inhibiting CSCs in breast cancer cells compared to chemotherapy (paclitaxel) (Dominguez-Gomez, et al., 2018). In vivo, Ivermectin alone is more effective than standard chemotherapy (gemcitabine) alone at reducing tumor weight and volume in pancreatic cancer (Lee, et al., 2022). Ivermectin is a very safe drug. In healthy volunteers, the single dose was increased to 2 mg/Kg, and no serious adverse reactions were found (Guzzo, et al., 2002). Demonstrated in another study, cancer patients who took Ivermectin at five times the standard dose (up to 1mg/kg) daily for up to 180 consecutive days had no serious adverse effects (de Castro, et al., 2020). In cases successfully treated with a total or partial combination of Ivermectin, dichloroacetate, and Omeprazole (plus Tamoxifen), Ivermectin inhibited tumor growth through mitochondrial dysfunction and led to apoptosis (Ishiguro, et al., 2022).

Benzimidazoles

Another family of drugs called Benzimidazoles holds promising anticancer capabilities including Fenbendazole and Mebendazole. Mebendazole and Fenbendazole are very structurally similar and generally just as effective in cancer (Bai, et al., 2011; Florio, et al., 2019; Schmit, 2013), in both in vitro and in vivo models (Song, et al., 2022). However, only Mebendazole is FDA approved for use in humans (Impax, 2016). Benzimidazoles have anticancer effects through microtubule polymerization, induction of apoptosis, cell cycle arrest (G2/M), anti-angiogenesis, blocking glucose (Son, et al., 2020) and glutamine pathways (Mukherjee, et al., 2023). Apoptosis is induced by mitochondrial injury and mediated by p53 expression (Mukhopadhyay, et al., 2002; Park, et al., 2022). Benzimidazoles also target CSCs and metastases (Son, et al., 2020; Song, et al., 2022) and, thus, the chemoresistant (cisplatin) cancer cells (Huang, et al., 2021). Mebendazole was more potent against gastric cancer cell lines than other well-known chemotherapeutic drugs (5-fluorouracil, oxaliplatin, gemcitabine, irinotecan, paclitaxel, cisplatin, etoposide and doxorubicin) in vitro (Pinto, et al., 2015). Whereas Mebendazole leads to significantly prolonged survival compared to standard chemotherapy (temozolomide) for glioblastoma multiforme in vivo (Bai, et al., 2011).

Mebendazole is established as a safe drug. In pediatric patients with hydatid disease, long-term Mebendazole treatment (50 mg/kg daily for 9–18 months) was demonstrated to be without significant side effects (Göçmen, et al., 1993). Patients receiving 1500 mg/day of Mebendazole for gliomas were also noted to be without toxicity from the drug (Chai, et al., 2021). Patients with treatment refractory gastrointestinal cancer participating in a phase 2 study using individualized doses of Mebendazole, up to 4 g/day, experienced no severe adverse effects (Mansoori, et al., 2021). A case of near-complete remission was reported in a patient with metastatic colon cancer after taking Mebendazole, following a failure of chemotherapeutic agents including Capecitabine, Oxaliplatin, Bevacizumab, Capecitabine and Irinotecan (Nygren & Larsson, 2014). In another case report, a 48-year-old man with adrenocortical carcinoma had disease progression with all systemic therapies. He was prescribed Mebendazole 100mg twice daily, as a single agent. His metastases initially regressed and subsequently remained stable. While receiving Mebendazole as a sole treatment for 19 months, his disease remained stable. He did not experience any clinically significant adverse effects, and his quality of life was satisfactory (Dobrosotskaya, et al., 2011). Similar results have been observed with Fenbendazole, three patients with stage IV cancer (genitourinary malignancies) were treated at a dose of 1,000 mg three times weekly for several months and experienced complete remission of the disease (Chiang, et al., 2021). Two of the three patients had experienced progression of metastatic disease despite several lines of treatment before starting Fenbendazole.

DON (6-diazo-5-oxo-L-norleucine)

DON is a glutamine-specific antagonist more potent than Benzimidazoles. DON has potent antitumor activity in vitro and in vivo (Olsen, et al., 2015). It specifically targets glutamine and also affects glucose uptake (Leone, et al., 2019). DON can specifically induce apoptosis in CSCs (Jariyal, et al., 2021), and target metastases (Shelton, et al., 2010). Low daily doses of DON are without toxicity (Lemberg, et al., 2018).

Dietary Interventions for Targeting the MSCC

Fasting

Fasting induces an improvement in mitochondrial activity through the increase of OxPhos, autophagy, and the inhibition of glycolysis and glutaminolysis (Bianchi, et al., 2015; Nencioni, et al., 2018; Tiwari, et al., 2022). Fasting can train the regeneration of “normal” stem cells (Mihaylova, et al., 2018), but it can also alter CSCs through autophagy (Nazio, et al., 2019). Inhibition or deprivation of glucose leads to the death of CSCs (De Francesco, et al., 2018). In vivo, fasting has anticancer effects and enhances the activity of drugs with which it is combined (Nencioni, et al., 2018). Taking into account the molecular mechanisms of cancer growth, researchers have affirmed that “… prescribing fasting as an anticancer drug may not be far away if large randomised clinical trials consolidate its safety and efficacy” (Deligiorgi, et al., 2020).

Ketogenic Diet and Ketone Metabolic Therapy (KMT)

Therapeutic ketosis given as a ketogenic diet or ketone metabolic therapy (KMT) inhibits cancer stem cell growth, restores apoptosis (Ji, et al., 2020), and increases cellular respiration (Greco, et al., 2016). The ketogenic diet exhibits antitumor effects both in vitro and in vivo, primarily by inhibiting the glycolysis pathway in various types of cancer (Weber, et al., 2018; Weber, et al., 2020), and its efficacy has been demonstrated in humans with glioblastoma mutiforme (Elsakka, et al., 2018; Zuccoli, et al., 2010). The maximum therapeutic benefits of DON and Mebendazole occurred only when the drugs were administered together with a ketogenic diet (Mukherjee, et al., 2019; Mukherjee, et al., 2023). Moreover, the association between a ketogenic diet and DON reduces DON toxicity (Mukherjee, et al., 2019). A ketogenic diet or fasting could inhibit the fuels necessary for cancer cells (glucose and glutamine) while also increasing the activity of OxPhos (Bianchi, et al., 2015). A case study reported the survival of a patient with grade IV glioblastoma living more than 6 years after diagnosis, treated with surgical reduction and a ketogenic diet under therapeutic ketosis without chemoradiotherapy (Seyfried, Shivane, et al., 2021). Foster analyzed 200 cases of spontaneous cancer regression, and showed that 87% made a major change in diet, primarily vegetarian in nature, 55% used some form of detoxification, and 65% used nutritional supplements (Foster, 1988). The goal with the ketogenic diet and ketone metabolic therapy is to simultaneously restrict the glycolysis and glutaminolysis pathways while at the same time transition the body into a state of ketosis to target the cancer cells – both CSCs and non-cancer stem cells. In addition to metabolic ketosis, ketone supplementation studies have demonstrated that ketones independently enhance mitochondrial function (Woolf, et al., 2016; Seyfried, et al., 2017) and suppress tumor growth by targeting metastasis and most hallmarks of cancer (Poff, et al., 2014; Poff, et al., 2019).

Additional Therapeutic Considerations

Press-Pulse Therapy

Press-Pulse therapy offers two-axis therapy. The “Press” axis, which consists of following a ketogenic diet associated with stress management. And a Pulse axis, which combines inhibition of glycolysis by 2-deoxyglucose (2-DG), inhibition of glutaminolysis by DON (6-diazo-5-oxo-L-norleucine), and hyperbaric oxygen therapy (HBOT) to reverse hypoxia and induce cancer-specific oxidative stress (Seyfried, et al. 2017). The metabolic theory underlying the Press-Pulse therapy is the closest to the proposed MSCC theory.

Physical Activity

Diabetes and obesity are risk factors for many cancers (Grant, 2024), probably through the alteration of OxPhos (Lewis, et al., 2019), promote CSCs (Hillers-Ziemer, et al., 2020) and the increase of the Warburg effect (Zhang & Le, 2021). Thus, physical activity may confer a protective role. Endurance exercises increase the volume of mitochondria, which improves mitochondrial respiration (Baldwin, et al., 1972; Jacobs & Lundby, 2013) and its protective effects on healthy cells (Kolodziej & O’Halloran, 2021). Exercise also decreases glycolytic activity (Gibb, et al., 2017). ATP production and mitochondrial respiration are highest during regular low to moderate intensity training (Flockhart, et al., 2021). Physical activity supports tissue regeneration, in part with stem cells (Liu, C., et al., 2023). Specifically concerning cancer cells, physical activity inhibits their proliferation and induces apoptosis (Wang & Zhou, 2021).

Hyperbaric Oxygen therapy (HBOT)

Hypoxia is a critical characteristic of malignant tumors and involves enhanced cell survival, angiogenesis, glycolysis and glutaminolysis metabolism, and metastasis. There is evidence that implies oxygen is a drug, dependent upon the dose (Poff, et al., 2016) and that HBOT has tumor-inhibitory effects, especially when combined with KMT (Seyfried, et al., 2014). HBOT exhibits potent antitumor activity both in vitro and in vivo, whether used alone or in combination (Moen & Stuhr, 2012). Tumor cells may adapt to ischemic and low nutrient microenvironments by three main adaptations: the angiogenic switch, deregulation of apoptosis, and the metabolism shift (Daruwalla & Christophi, 2006). HBOT can target CSCs and metastases (Liu, et al., 2021; Xiong, et al., 2023) and increase OxPhos (Hadanny, et al., 2022). KMT is synergistic with HBOT and elicits a potent synergistic effect on suppressing tumor growth and metastatic spread in pre-clinical models of metastatic cancer and human case reports (Elsakka, et al., 2018; Poff, et al., 2015; Poff, et al., 2019).

Proposed Hybrid Orthomolecular Protocol

Based on our review of the scientific literature, the following protocol combining orthomolecules, drugs and additional therapies for targeting the MSCC in cancer treatment is proposed:

Intravenous Vitamin C
Intermediate- and high-grade cancers: Dose of 1.5g/kg/day, 2-3x per week (Fan, et al., 2023).
Established as a non-toxic dose for cancer patients (Wang, F., et al., 2019).
.
Oral Vitamin D
All cancer grades: Dose of 50,000 IU/day for patients with a blood level ≤ 30ng/mL; 25,000 IU/day for levels 30-60ng/mL; and 5000 IU/day for levels 60-80ng/mL.
Established as a non-toxic dose (Cannon, et al., 2016; Ghanaati, et al., 2020; McCullough, et al., 2019).
It is necessary to reach a blood level of 80 ng/mL of vitamin D (25-hydroxyvitamine D (25(OH) D) (Kennel, et al., 2010; Mohr, et al., 2014; Mohr, et al., 2015). This level is non-toxic (Holick, et al., 2011). Once this level is reached it must be maintained with a reduced daily dosage of ≈ 2000 IU/day (Ekwaru, et al., 2014). The vitamin D blood concentration should be measured every two weeks for high doses and monthly for lower doses.
.
Zinc
All cancer grades: Dose of 1 mg/kg/day is established as a non-toxic dose for cancer patients (Hoppe, et al., 2021; Lin, et al., 2006). The reference range for serum zinc concentration is 80 to 120 μg/dL (Mashhadi, et al., 2016; Yokokawa, et al., 2020). Once this level is reached it must be maintained with a reduced daily dosage of 5mg/day (Li, et al., 2022). The zinc blood concentration should be measured monthly.
.
Ivermectin
Low-grade cancers: Dose of 0.5mg/kg, 3x per week (Guzzo, et al., 2002).
Intermediate-grade cancers: Dose of 1mg/kg, 3x per week (Guzzo, et al., 2002).
High-grade cancers: Dose from 1 mg/kg/day (de Castro, et al., 2020) to 2 mg/kg/day (Guzzo, et al., 2002).
All these doses have been established as tolerable for humans (Guzzo, et al., 2002).
.
Benzimidazoles and DON
Low-grade cancers: Mebendazole: Dose of 200 mg/day (Dobrosotskaya, et al., 2011).
Intermediate-grade cancers: Mebendazole: Dose of 400 mg/day (Chai, et al., 2021).
High-grade cancers: Mebendazole dose of 1,500 mg/day (Son, et al., 2020) or Fenbendazole 1,000 mg 3x per week (Chiang, et al., 2021).
All these doses have been established as tolerable for humans (Chai, et al., 2021; Chiang, et al., 2021; Son, et al., 2020). Benzimidazoles can be replaced or combined with DON, administered without toxicity; intravenously or intramuscularly: 0.2 to 0.6 mg/kg once daily; or orally: 0.2 to 1.1 mg/kg once daily (Lemberg, et al., 2018; Rais, et al., 2022). Benzimidazoles are much easier to obtain than DON. However, for metastatic cancers, which rely heavily on glutamine (Seyfried, et al., 2020), a combination of DON and Benzimidazoles should be considered (Mukherjee, et al., 2023).
.
Dietary Interventions
All cancer grades: Ketogenic diet (low carbohydrate-high fat diet, 900 to 1500 kcal/day) (Weber, et al., 2020).
Ketone metabolic therapy consists of approximately 60-80% fat, 15-25% protein and 5-10% fibrous carbohydrates. Adequate hydration and single-ingredient whole food ketogenic meals are necessary to achieve a glucose ketone index (GKI) score of 2.0 or below (Meidenbauer, et al., 2015; Seyfried, Shivane, et al., 2021). GKI should be measured 2–3 hours postprandial, twice a day if possible (Meidenbauer, et al., 2015; Seyfried, Shivane, et al., 2021).
Intermediate- and high-grade cancers: The ketogenic diet should be coupled with a water fast for 3 to 7 consecutive days in advanced cancers (Phillips, et al., 2022; Arora, et al., 2023). The water fast should be repeated several times (≈ every 3-4 weeks) throughout the treatment (Nencioni, et al., 2018), but fasting needs to be undertaken cautiously in individuals using certain drugs and those with < 20 BMI, to prevent loss of lean body mass. For patients who can not fast, the Fasting-Mimicking Diet (300 to 1,100 kcal/day of broths, soups, juices, nut bars, and herbal teas) can be used (Nencioni, et al., 2018).
.
Additional Therapeutics
All cancer grades: Moderate physical activity, 3x per week. Increased heart and respiratory rate for a period of 45 to 75 minutes (Bull, et al., 2020) with activities such as cycling, running, swimming, etc.
Intermediate- and high-grade cancers or individuals who are unable to engage in physical activity: Hyperbaric oxygen therapy, 1.5 to 2.5 ATA for 45 to 60 minutes 2-3x per week (Gonzalez, et al., 2018; Poff, et al., 2015).

The protocol should be followed for an average duration of 12 weeks, regardless of cancer type. The analysis of the interactions between each of the molecules revealed no contraindications to the combination of these substances (ANSM, 2023; CRAT, 2024; Lemberg, et al., 2018; Vidal, 2024). The treatment dosage and duration can be adjusted by the physician according to the individual patient, their ability to obtain the various molecules, and the treatment results. Adaptation of the protocol to include additional molecules to restore health, could be considered by the physician. These may include: vitamin K2 (Xv, et al., 2018), vitamin E (Abraham, et al., 2019), coenzyme Q10 (Liaghat, et al., 2024), methylene blue (da Veiga Moreira, et al., 2024), niacinamide (Yousef, et al., 2022), riboflavin (Suwannasom, et al., 2020), Artemisinin + 5-aminolevulinic acid (to cause porphyrin accumulation) (Adapa, et al., 2024), melatonin (Mocayar, et al., 2020), NADH (Medjdoub, et al., 2016), and magnesium (Ashique, et al., 2023), as examples. However, antioxidant dosages should be avoided.

This additive and synergistic effect of this combination of orthomolecules, drugs, and additional therapies targets the MSCC by increasing OxPhos activity in healthy mitochondria, offering protective action for these cells. However, in cancer cells, both CSCs and non-CSCs, the pro-oxidant effect of the combination induces apoptosis. Additionally, this protocol specifically targets fermentable fuels, CSCs and macrophages, and thus metastases. In brief, the key points of the MSCC. Therefore, comparative studies need to be conducted in both animals and humans to evaluate the effectiveness and safety of this hybrid protocol against standard therapies.

Conclusion

The mitochondrial-stem cell connection could be a key element in the therapeutic approach to cancer. In light of current knowledge, we have selected and propose the use of specific orthomolecules, drugs and other therapies for their potential to revive cellular OxPhos activity, and target CSCs, glycolysis and glutaminolysis. These are also aimed at addressing metastases created by fusion hybridization between cancer stem cells and macrophages. Numerous experiments in cells, animals, and humans support the role of targeting the MSCC in both the prevention and treatment of cancer.

Conflicts of Interest

The authors declare no conflicts of interest.

Acknowledgement

This manuscript is dedicated in memory of our colleague and friend Dr. Michael J. Gonzalez. He left a lasting impact on orthomolecular medicine, and we will strive to honor him through the publication of what will be one of his final contributions.

References

Abraham, A., Kattoor, A. J., Saldeen T., and Mehta, J. L. (2019). “Vitamin E and its anticancer effects.” Crit Rev Food Sci Nutr. 59(17): 2831-2838. https://doi.org/10.1080/10408398.2018.1474169.

Adams, J. M., and Strasser, A. (2008). “Is tumor growth sustained by rare cancer stem cells or dominant clones?” Cancer Res. 68(11): 4018-4021. https://doi.org/10.1158/0008-5472.can-07-6334.

Adapa, S. R., Hunter, G. A., Amin, N. E., Marinescu, C., Borsky, A., Sagatys, E. M., Sebti, S. M., Reuther, G. W., Ferreira, G. C., and Jiang, R. H. (2024). “Porphyrin overdrive rewires cancer cell metabolism.” Life Sci Alliance. 7(7). https://doi.org/10.26508/lsa.202302547.

Aguilera, O., Muñoz-Sagastibelza, M., Torrejón, B., Borrero-Palacios, A., Del Puerto-Nevado, L., Martínez-Useros, J., Rodriguez-Remirez, M., Zazo, S., García, E., Fraga, M., Rojo, F., and García-Foncillas, J. (2016). “Vitamin C uncouples the Warburg metabolic switch in KRAS mutant colon cancer.” Oncotarget. 7(30): 47954-47965. https://doi.org/10.18632/oncotarget.10087.

Aljohar, A. Y., Muteeb, G., Zia, Q., Siddiqui, S., Aatif, M., Farhan, M., Khan, M. F., Alsultan, A., Jamal, A., Alshoaibi, A., Ahmad, E., Alam, M. W., Arshad, M., and Ahamed, M. I. (2022). “Anticancer effect of zinc oxide nanoparticles prepared by varying entry time of ion carriers against A431 skin cancer cells in vitro.” Front Chem. 10: 1069450. https://doi.org/10.3389/fchem.2022.1069450.

ANSM. (2023). “Thesaurus des interactions médicamenteuses.”. Available online: https://ansm.sante.fr/uploads/2023/09/15/20230915-thesaurus-interactions-medicamenteuses-septembre-2023.pdf (accessed on septembre 05, 2024).

Arora, N., Pulimamidi, S., Yadav, H., Jain, S., Glover, J., Dombrowski, K., Hernandez, B., Sarma, A. K., and Aneja, R. (2023). “Intermittent fasting with ketogenic diet: A combination approach for management of chronic diseases.” Clin Nutr ESPEN. 54: 166-174. https://doi.org/10.1016/j.clnesp.2023.01.024.

Ashique, S., Kumar, S., Hussain, A., Mishra, N., Garg, A., Gowda, B. H. J., Farid, A., Gupta, G., Dua, K., and Taghizadeh-Hesary, F. (2023). “A narrative review on the role of magnesium in immune regulation, inflammation, infectious diseases, and cancer.” J Health Popul Nutr. 42(1): 74. https://doi.org/10.1186/s41043-023-00423-0.

Averbeck, D., and Rodriguez-Lafrasse, C. (2021). “Role of Mitochondria in Radiation Responses: Epigenetic, Metabolic, and Signaling Impacts.” Int J Mol Sci. 22(20). https://doi.org/10.3390/ijms222011047.

Bai, R. Y., Staedtke, V., Aprhys, C. M., Gallia, G. L., & Riggins, G. J. (2011). Antiparasitic mebendazole shows survival benefit in 2 preclinical models of glioblastoma multiforme. Neuro Oncol. 13(9), 974-982. https://doi.org/10.1093/neuonc/nor077

Baldwin, K. M., Klinkerfuss, G. H., Terjung, R. L., Molé, P. A., and Holloszy, J. O. (1972). “Respiratory capacity of white, red, and intermediate muscle: adaptative response to exercise.” Am J Physiol. 222(2): 373-378. https://doi.org/10.1152/ajplegacy.1972.222.2.373.

Bianchi, G., Martella, R., Ravera, S., Marini, C., Capitanio, S., Orengo, A., Emionite, L., Lavarello, C., Amaro, A., Petretto, A., Pfeffer, U., Sambuceti, G., Pistoia, V., Raffaghello, L., and Longo, V. D. (2015). “Fasting induces anti-Warburg effect that increases respiration but reduces ATP-synthesis to promote apoptosis in colon cancer models.” Oncotarget. 6(14): 11806-11819. https://doi.org/10.18632/oncotarget.3688.

Bonuccelli, G., De Francesco, E. M., de Boer, R., Tanowitz, H. B., and Lisanti, M. P. (2017). “NADH autofluorescence, a new metabolic biomarker for cancer stem cells: Identification of Vitamin C and CAPE as natural products targeting “stemness”.” Oncotarget. 8(13): 20667-20678. https://doi.org/10.18632/oncotarget.15400.

Bull, F. C., Al-Ansari, S. S., Biddle, S., Borodulin, K., Buman, M. P., Cardon, G., Carty, C., Chaput, J. P., Chastin, S., Chou, R., Dempsey, P. C., DiPietro, L., Ekelund, U., Firth, J., Friedenreich, C. M., Garcia, L., Gichu, M., Jago, R., Katzmarzyk, P. T., Lambert, E., Leitzmann, M., Milton, K., Ortega, F. B., Ranasinghe, C., Stamatakis, E., Tiedemann, A., Troiano, R. P., van der Ploeg, H. P., Wari, V., and Willumsen, J. F. (2020). “World Health Organization 2020 guidelines on physical activity and sedentary behaviour.” Br J Sports Med. 54(24): 1451-1462. https://doi.org/10.1136/bjsports-2020-102955.

Butt, G., Farooqi, A. A., Adylova, A., Attar, R., Yilmaz, S., Konysbayevna, K. K., Sabitaliyevich, U. Y., Gasparri, M. L., and Xu, B. (2020). “Vitamin C as an Anticancer Agent: Regulation of Signaling Pathways.” Curr Top Med Chem. 20(21): 1868-1875. https://doi.org/10.2174/1568026620666200710102841.

Cameron, E., and Pauling, L. (1978). “Supplemental ascorbate in the supportive treatment of cancer: reevaluation of prolongation of survival times in terminal human cancer.” Proc Natl Acad Sci U S A. 75(9): 4538-4542. https://doi.org/10.1073/pnas.75.9.4538.

Cannon, T. L., Ford, J., Hester, D., & Trump, D. L. (2016). The Incidental Use of High-Dose Vitamin D3 in Pancreatic Cancer. In Case Rep Pancreat Cancer. 2(1): 32-35. https://doi.org/10.1089/crpc.2016.0003

Capp, J. P. (2019). “Cancer Stem Cells: From Historical Roots to a New Perspective.” J Oncol. 2019: 5189232. https://doi.org/10.1155/2019/5189232.

Cardone, R. A., Casavola, V., and Reshkin, S. J. (2005). “The role of disturbed pH dynamics and the Na+/H+ exchanger in metastasis.” Nat Rev Cancer. 5(10): 786-795. https://doi.org/10.1038/nrc1713.

Chai, J. Y., Jung, B. K., and Hong, S. J. (2021). “Albendazole and Mebendazole as Anti-Parasitic and Anti-Cancer Agents: an Update.” Korean J Parasitol. 59(3): 189-225. https://doi.org/10.3347/kjp.2021.59.3.189.

Chakraborti, C. K. (2011). “Vitamin D as a promising anticancer agent.” Indian J Pharmacol. 43(2): 113-120. https://doi.org/10.4103/0253-7613.77335.

Chandler, P. D., Chen, W. Y., Ajala, O. N., Hazra, A., Cook, N., Bubes, V., Lee, I. M., Giovannucci, E. L., Willett, W., Buring, J. E., and Manson, J. E. (2020). “Effect of Vitamin D3 Supplements on Development of Advanced Cancer: A Secondary Analysis of the VITAL Randomized Clinical Trial.” JAMA Netw Open. 3(11): e2025850. https://doi.org/10.1001/jamanetworkopen.2020.25850.

Chen, M., Ding, Y., Ke, Y., Zeng, Y., Liu, N., Zhong, Y., Hua, X., Li, Z., Xiong, Y., Wu, C., and Yu, H. (2020). “Anti-tumour activity of zinc ionophore pyrithione in human ovarian cancer cells through inhibition of proliferation and migration and promotion of lysosome-mitochondrial apoptosis.” Artif Cells Nanomed Biotechnol. 48(1): 824-833. https://doi.org/10.1080/21691401.2020.1770266.

Chen, Q., Espey, M. G., Krishna, M. C., Mitchell, J. B., Corpe, C. P., Buettner, G. R., Shacter, E., and Levine, M. (2005). “Pharmacologic ascorbic acid concentrations selectively kill cancer cells: action as a pro-drug to deliver hydrogen peroxide to tissues.” Proc Natl Acad Sci U S A. 102(38): 13604-13609. https://doi.org/10.1073/pnas.0506390102.

Chen, Q., Espey, M. G., Sun, A. Y., Pooput, C., Kirk, K. L., Krishna, M. C., Khosh, D. B., Drisko, J., and Levine, M. (2008). “Pharmacologic doses of ascorbate act as a prooxidant and decrease growth of aggressive tumor xenografts in mice.” Proc Natl Acad Sci U S A. 105(32): 11105-11109. https://doi.org/10.1073/pnas.0804226105.

Chiang, R., Syed, A., Wright, J., Montgomery, B., & Srinivas, S. (2021). Fenbendazole Enhancing Anti-Tumor Effect: A Case Series. Clin Oncol Case Rep. 4(2).

Chu, J., Li, Y., He, M., Zhang, H., Yang, L., Yang, M., Liu, J., Cui, C., Hong, L., Hu, X., Zhou, L., Li, T., Li, C., Fan, H., Jiang, G., and Lang, T. (2023). “Zinc finger and SCAN domain containing 1, ZSCAN1, is a novel stemness-related tumor suppressor and transcriptional repressor in breast cancer targeting TAZ.” Front Oncol. 13: 1041688. https://doi.org/10.3389/fonc.2023.1041688.

Costello, L. C., and Franklin, R. B. (2017). “Decreased zinc in the development and progression of malignancy: an important common relationship and potential for prevention and treatment of carcinomas.” Expert Opin Ther Targets. 21(1): 51-66. https://doi.org/10.1080/14728222.2017.1265506.

CRAT. 2024. Available online: https://www.lecrat.fr/ (accessed on septembre 05, 2024).

da Veiga Moreira, J., Nleme, N., Schwartz, L., Leclerc-Desaulniers, K., Carmona, E., Mes-Masson, A. M., and Jolicoeur, M. (2024). “Methylene Blue Metabolic Therapy Restrains In Vivo Ovarian Tumor Growth.” Cancers (Basel). 16(2). https://doi.org/10.3390/cancers16020355.

Daruwalla, J., and Christophi, C. (2006). “Hyperbaric oxygen therapy for malignancy: a review.” World J Surg. 30(12): 2112-2131. https://doi.org/10.1007/s00268-006-0190-6.

de Castro, C. G. Jr., Gregianin, L. J., and Burger, J. A. (2020). “Continuous high-dose ivermectin appears to be safe in patients with acute myelogenous leukemia and could inform clinical repurposing for COVID-19 infection.” Leuk Lymphoma. 61(10): 2536-2537. https://doi.org/10.1080/10428194.2020.1786559.

De Francesco, E. M., Sotgia, F., and Lisanti, M. P. (2018). “Cancer stem cells (CSCs): metabolic strategies for their identification and eradication.” Biochem J. 475(9): 1611-1634. https://doi.org/10.1042/bcj20170164.

Deligiorgi, M. V., Liapi, C., and Trafalis, D. T. (2020). “How Far Are We from Prescribing Fasting as Anticancer Medicine?” Int J Mol Sci. 21(23). https://doi.org/10.3390/ijms21239175.

Del Paggio, J. C., Berry, J. S., Hopman, W. M., Eisenhauer, E. A., Prasad, V., Gyawali, B., & Booth, C. M. (2021). Evolution of the Randomized Clinical Trial in the Era of Precision Oncology. JAMA Oncology. 7(5): 728-734. https://doi.org/10.1001/jamaoncol.2021.0379

Deruelle, F., and Baron, B. (2008). “Vitamin C: is supplementation necessary for optimal health?” J Altern Complement Med. 14(10): 1291-1298. https://doi.org/10.1089/acm.2008.0165.

Dobrosotskaya, I. Y., Hammer, G. D., Schteingart, D. E., Maturen, K. E., and Worden, F. P. (2011). “Mebendazole monotherapy and long-term disease control in metastatic adrenocortical carcinoma.” Endocr Pract. 17(3): e59-62. https://doi.org/10.4158/ep10390.cr.

Dominguez-Gomez, G., Chavez-Blanco, A., Medina-Franco, J. L., Saldivar-Gonzalez, F., Flores-Torrontegui, Y., Juarez, M., Díaz-Chávez, J., Gonzalez-Fierro, A., and Dueñas-González, A. (2018). “Ivermectin as an inhibitor of cancer stem‑like cells.” Mol Med Rep. 17(2): 3397-3403. https://doi.org/10.3892/mmr.2017.8231.

Dressler, R., Laut, J., Lynn, R. I., and Ginsberg, N. (1995). “Long-term high dose intravenous calcitriol therapy in end-stage renal disease patients with severe secondary hyperparathyroidism.” Clin Nephrol. 43(5): 324-331.

Ekwaru, J. P., Zwicker, J. D., Holick, M. F., Giovannucci, E., and Veugelers, P. J. (2014). “The importance of body weight for the dose response relationship of oral vitamin D supplementation and serum 25-hydroxyvitamin D in healthy volunteers.” PLoS One. 9(11): e111265. https://doi.org/10.1371/journal.pone.0111265.

Elliott, R. L., Jiang, X. P., & Head, J. F. (2012). Mitochondria organelle transplantation: introduction of normal epithelial mitochondria into human cancer cells inhibits proliferation and increases drug sensitivity. Breast Cancer Res Treat. 136(2), 347-354. https://doi.org/10.1007/s10549-012-2283-2

Elsakka, A. M. A., Bary, M. A., Abdelzaher, E., Elnaggar, M., Kalamian, M., Mukherjee, P., and Seyfried, T. N. (2018). “Management of Glioblastoma Multiforme in a Patient Treated With Ketogenic Metabolic Therapy and Modified Standard of Care: A 24-Month Follow-Up.” Front Nutr. 5: 20. https://doi.org/10.3389/fnut.2018.00020.

Fakih, M. G., Trump, D. L., Muindi, J. R., Black, J. D., Bernardi, R. J., Creaven, P. J., Schwartz, J., Brattain, M. G., Hutson, A., French, R., and Johnson, C. S. (2007). “A phase I pharmacokinetic and pharmacodynamic study of intravenous calcitriol in combination with oral gefitinib in patients with advanced solid tumors.” Clin Cancer Res. 13(4): 1216-1223. https://doi.org/10.1158/1078-0432.ccr-06-1165.

Fan, D., Liu, X., Shen, Z., Wu, P., Zhong, L., and Lin, F. (2023). “Cell signaling pathways based on vitamin C and their application in cancer therapy.” Biomed Pharmacother. 162: 114695. https://doi.org/10.1016/j.biopha.2023.114695.

Feng, Y., Wang, J., Cai, B., Bai, X., & Zhu, Y. (2022). Ivermectin accelerates autophagic death of glioma cells by inhibiting glycolysis through blocking GLUT4 mediated JAK/STAT signaling pathway activation. Environ Toxicol. 37(4): 754-764. https://doi.org/10.1002/tox.23440

Flockhart, M., Nilsson, L. C., Tais, S., Ekblom, B., Apró, W., and Larsen, F. J. (2021). “Excessive exercise training causes mitochondrial functional impairment and decreases glucose tolerance in healthy volunteers.” Cell Metab. 33(5): 957-970.e956. https://doi.org/10.1016/j.cmet.2021.02.017.

Florio, R., Veschi, S., di Giacomo, V., Pagotto, S., Carradori, S., Verginelli, F.,…De Lellis, L. (2019). The Benzimidazole-Based Anthelmintic Parbendazole: A Repurposed Drug Candidate That Synergizes with Gemcitabine in Pancreatic Cancer. Cancers (Basel). 11(12). https://doi.org/10.3390/cancers11122042

Foster, H. (1988 ). “Lifestyle changes and the “Spontaneous” regression of cancer: An initial computer analysis.” International Journal of Biosocial Research. 10(1): 17-33.

Gelbard, A. (2022). “Zinc in Cancer Therapy Revisited.” Isr Med Assoc J. 24(4): 258-262.

Ghanaati, S., Choukroun, J., Volz, U., Hueber, R., Mourao, C. F., Sader, R., Kawase-Koga, Y., Mazhari, R., Amrein, K., Meybohm, P., and Al-Maawi, S. (2020). “One hundred years after Vitamin D discovery: Is there clinical evidence for supplementation doses?” International Journal of Growth Factors and Stem Cells in Dentistry. 3: 3. https://doi.org/10.4103/GFSC.GFSC_4_20.

Gibb, A. A., Epstein, P. N., Uchida, S., Zheng, Y., McNally, L. A., Obal, D., Katragadda, K., Trainor, P., Conklin, D. J., Brittian, K. R., Tseng, M. T., Wang, J., Jones, S. P., Bhatnagar, A., and Hill, B. G. (2017). “Exercise-Induced Changes in Glucose Metabolism Promote Physiological Cardiac Growth.” Circulation. 136(22): 2144-2157. https://doi.org/10.1161/circulationaha.117.028274.

Gillies, R. J., Raghunand, N., Karczmar, G. S., and Bhujwalla, Z. M. (2002). “MRI of the tumor microenvironment.” J Magn Reson Imaging. 16(4): 430-450. https://doi.org/10.1002/jmri.10181.

Gonzalez, M., Seyfried. T.N., Nicolson, G., Barclay, B., Matta, J., Vasquez, A., D’Agostino. D.P., Olalde, J., Duconge, J., Hunninghake, R., Berdiel, M., and Cintron. A. (2018). “Mitochondrial correction: a new therapeutic paradigm for cancer and degenerative diseases.” J Orthomol Med. 33: 1-20.

Gonzalez, M. J., Miranda-Massari, J. R., and Olalde, J. (2023). Chapter 9 – Vitamin C and mitochondrial function in health and exercise. Molecular Nutrition and Mitochondria. S. M. Ostojic, Academic Press: 225-242.

Gonzalez, M. J., Rosario-Pérez, G., Guzmán, A. M., Miranda-Massari, J. R., Duconge, J., Lavergne, J., Fernandez, N., Ortiz, N., Quintero, A., Mikirova, N., Riordan, N. H., and Ricart, C. M. (2010). “Mitochondria, Energy and Cancer: The Relationship with Ascorbic Acid.” J Orthomol Med. 25(1): 29-38.

Gorini, S., De Angelis, A., Berrino, L., Malara, N., Rosano, G., and Ferraro, E. (2018). “Chemotherapeutic Drugs and Mitochondrial Dysfunction: Focus on Doxorubicin, Trastuzumab, and Sunitinib.” Oxid Med Cell Longev. 2018: 7582730. https://doi.org/10.1155/2018/7582730.

Grant, W. B. (2024) “Cancer Incidence Rates in the US in 2016–2020 with Respect to Solar UVB Doses, Diabetes and Obesity Prevalence, Lung Cancer Incidence Rates, and Alcohol Consumption: An Ecological Study.” Nutrients. 16(10) https://doi.org/10.3390/nu16101450.

Greco, T., Glenn, T. C., Hovda, D. A., and Prins, M. L. (2016). “Ketogenic diet decreases oxidative stress and improves mitochondrial respiratory complex activity.” J Cereb Blood Flow Metab. 36(9): 1603-1613. https://doi.org/10.1177/0271678×15610584.

Guzzo, C. A., Furtek, C. I., Porras, A. G., Chen, C., Tipping, R., Clineschmidt, C. M., Sciberras, D. G., Hsieh, J. Y., and Lasseter, K. C. (2002). “Safety, tolerability, and pharmacokinetics of escalating high doses of ivermectin in healthy adult subjects.” J Clin Pharmacol. 42(10): 1122-1133. https://doi.org/10.1177/009127002401382731.

Göçmen, A., Toppare, M. F., and Kiper, N. (1993). “Treatment of hydatid disease in childhood with mebendazole.” Eur Respir J. 6(2): 253-257.

Hadanny, A., Hachmo, Y., Rozali, D., Catalogna, M., Yaakobi, E., Sova, M., Gattegno, H., Abu Hamed, R., Lang, E., Polak, N., Friedman, M., Finci, S., Zemel, Y., Bechor, Y., Gal, N., and Efrati, S. (2022). “Effects of Hyperbaric Oxygen Therapy on Mitochondrial Respiration and Physical Performance in Middle-Aged Athletes: A Blinded, Randomized Controlled Trial.” Sports Med Open. 8(1): 22. https://doi.org/10.1186/s40798-021-00403-w.

Hanahan, D., and Weinberg, R. A. (2000). “The hallmarks of cancer.” Cell. 100(1): 57-70. https://doi.org/10.1016/s0092-8674(00)81683-9.

Hillers-Ziemer, L. E., McMahon, R. Q., Hietpas, M., Paderta, G., LeBeau, J., McCready, J., & Arendt, L. M. (2020). Obesity Promotes Cooperation of Cancer Stem-Like Cells and Macrophages to Enhance Mammary Tumor Angiogenesis. Cancers (Basel). 12(2). https://doi.org/10.3390/cancers12020502

Hohaus, S., Tisi, M. C., Bellesi, S., Maiolo, E., Alma, E., Tartaglia, G., Corrente, F., Cuccaro, A., D’Alo, F., Basile, U., Larocca, L. M., and De Stefano, V. (2018). “Vitamin D deficiency and supplementation in patients with aggressive B-cell lymphomas treated with immunochemotherapy.” Cancer Med. 7(1): 270-281. https://doi.org/10.1002/cam4.1166.

Holick, M. F., Binkley, N. C., Bischoff-Ferrari, H. A., Gordon, C. M., Hanley, D. A., Heaney, R. P., Murad, M. H., and Weaver, C. M. (2011). “Evaluation, treatment, and prevention of vitamin D deficiency: an Endocrine Society clinical practice guideline.” J Clin Endocrinol Metab. 96(7): 1911-1930. https://doi.org/10.1210/jc.2011-0385.

Holm, E., Hagmüller, E., Staedt, U., Schlickeiser, G., Günther, H., Leweling, H., Tokus, M., and Kollmar, H. (1995). “Substrate balances across colonic carcinomas in Humans.” Cancer research. 55: 1373-1378.

Hoppe, C., Kutschan, S., Dörfler, J., Büntzel, J., and Huebner, J. (2021). “Zinc as a complementary treatment for cancer patients: a systematic review.” Clin Exp Med. 21(2): 297-313. https://doi.org/10.1007/s10238-020-00677-6.

Huang, L., Zhao, L., Zhang, J., He, F., Wang, H., Liu, Q.,…Tang, L. (2021). Antiparasitic mebendazole (MBZ) effectively overcomes cisplatin resistance in human ovarian cancer cells by inhibiting multiple cancer-associated signaling pathways. Aging (Albany NY). 13(13), 17407-17427. https://doi.org/10.18632/aging.203232

Impax. (2016). “Impax Receives Approval of EMVERM™(mebendazole) Chewable Tablets, 100 mg.”. Available online: https://s22.q4cdn.com/186279204/files/doc_news/archive/Impax-Receives-Approval-of-EMVERM-mebendazole-Chewable-Tablets-100-mg.pdf (accessed on septembre 05, 2024).

Ishiguro, T., Ishiguro, R. H., Ishiguro, M., Toki, A., and Terunuma, H. (2022). “Synergistic Anti-tumor Effect of Dichloroacetate and Ivermectin.” Cureus. 14(2): e21884. https://doi.org/10.7759/cureus.21884.

Jacobs, R. A., and Lundby, C. (2013). “Mitochondria express enhanced quality as well as quantity in association with aerobic fitness across recreationally active individuals up to elite athletes.” J Appl Physiol (1985). 114(3): 344-350. https://doi.org/10.1152/japplphysiol.01081.2012.

Jagust, P., de Luxán-Delgado, B., Parejo-Alonso, B., and Sancho, P. (2019). “Metabolism-Based Therapeutic Strategies Targeting Cancer Stem Cells.” Front Pharmacol. 10: 203. https://doi.org/10.3389/fphar.2019.00203.

Jariyal, H., Gupta, C., Andhale, S., Gadge, S., and Srivastava, A. (2021). “Comparative stemness and differentiation of luminal and basal breast cancer stem cell type under glutamine-deprivation.” J Cell Commun Signal. 15(2): 207-222. https://doi.org/10.1007/s12079-020-00603-1.

Ji, C. C., Hu, Y. Y., Cheng, G., Liang, L., Gao, B., Ren, Y. P., Liu, J. T., Cao, X. L., Zheng, M. H., Li, S. Z., Wan, F., Han, H., and Fei, Z. (2020). “A ketogenic diet attenuates proliferation and stemness of glioma stem‑like cells by altering metabolism resulting in increased ROS production.” Int J Oncol. 56(2): 606-617. https://doi.org/10.3892/ijo.2019.4942.

Jiang, L., Sun, Y. J., Song, X. H., Sun, Y. Y., Yang, W. Y., Li, J., and Wu, Y. J. (2022). “Ivermectin inhibits tumor metastasis by regulating the Wnt/β-catenin/integrin β1/FAK signaling pathway.” Am J Cancer Res. 12(10): 4502-4519.

Juarez, M., Schcolnik-Cabrera, A., and Dueñas-Gonzalez, A. (2018). “The multitargeted drug ivermectin: from an antiparasitic agent to a repositioned cancer drug.” Am J Cancer Res. 8(2): 317-331.

Juarez, M., Schcolnik-Cabrera, A., Dominguez-Gomez, G., Chavez-Blanco, A., Diaz-Chavez, J., & Duenas-Gonzalez, A. (2020). Antitumor effects of ivermectin at clinically feasible concentrations support its clinical development as a repositioned cancer drug. Cancer Chemother Pharmacol. 85(6): 1153-1163. https://doi.org/10.1007/s00280-020-04041-z

Kanno, K., Akutsu, T., Ohdaira, H., Suzuki, Y., & Urashima, M. (2023). Effect of Vitamin D Supplements on Relapse or Death in a p53-Immunoreactive Subgroup With Digestive Tract Cancer: Post Hoc Analysis of the AMATERASU Randomized Clinical Trial. JAMA Netw Open. 6(8): e2328886. https://doi.org/10.1001/jamanetworkopen.2023.28886

Kc, S., Cárcamo, J. M., and Golde, D. W. (2005). “Vitamin C enters mitochondria via facilitative glucose transporter 1 (Glut1) and confers mitochondrial protection against oxidative injury.” Faseb j. 19(12): 1657-1667. https://doi.org/10.1096/fj.05-4107com.

Kennel, K. A., Drake, M. T., and Hurley, D. L. (2010). “Vitamin D deficiency in adults: when to test and how to treat.” Mayo Clin Proc. 85(8): 752-757; quiz 757-758. https://doi.org/10.4065/mcp.2010.0138.

Keum, N., Chen, Q. Y., Lee, D. H., Manson, J. E., and Giovannucci, E. (2022). “Vitamin D supplementation and total cancer incidence and mortality by daily vs. infrequent large-bolus dosing strategies: a meta-analysis of randomised controlled trials.” Br J Cancer. 127(5): 872-878. https://doi.org/10.1038/s41416-022-01850-2.

Kolodziej, F., and O’Halloran, K. D. (2021). “Re-Evaluating the Oxidative Phenotype: Can Endurance Exercise Save the Western World?” Antioxidants (Basel). 10(4). https://doi.org/10.3390/antiox10040609.

Ladanie, A., Schmitt, A. M., Speich, B., Naudet, F., Agarwal, A., Pereira, T. V.,…Hemkens, L. G. (2020). Clinical Trial Evidence Supporting US Food and Drug Administration Approval of Novel Cancer Therapies Between 2000 and 2016. JAMA Netw Open. 3(11): e2024406. https://doi.org/10.1001/jamanetworkopen.2020.24406

Lee, D. C., Ta, L., Mukherjee, P., Duraj, T., Domin, M., Greenwood, B., Karmacharya, S., Narain, N. R., Kiebish, M., Chinopoulos, C., and Seyfried, T. N. (2024). “Amino Acid and Glucose Fermentation Maintain ATP Content in Mouse and Human Malignant Glioma Cells.” bioRxiv: 2024.2004.2018.589922. https://doi.org/10.1101/2024.04.18.589922.

Lee, D. E., Kang, H. W., Kim, S. Y., Kim, M. J., Jeong, J. W., Hong, W. C.,…Park, J. S. (2022). Ivermectin and gemcitabine combination treatment induces apoptosis of pancreatic cancer cells via mitochondrial dysfunction. Front Pharmacol. 13, 934746. https://doi.org/10.3389/fphar.2022.934746

Lee, Y. (2023). “Role of Vitamin C in Targeting Cancer Stem Cells and Cellular Plasticity.” Cancers (Basel). 15(23). https://doi.org/10.3390/cancers15235657.

Lemberg, K. M., Vornov, J. J., Rais, R., and Slusher, B. S. (2018). “We’re Not “DON” Yet: Optimal Dosing and Prodrug Delivery of 6-Diazo-5-oxo-L-norleucine.” Mol Cancer Ther. 17(9): 1824-1832. https://doi.org/10.1158/1535-7163.mct-17-1148.

Leone, R. D., Zhao, L., Englert, J. M., Sun, I. M., Oh, M. H., Sun, I. H., Arwood, M. L., Bettencourt, I. A., Patel, C. H., Wen, J., Tam, A., Blosser, R. L., Prchalova, E., Alt, J., Rais, R., Slusher, B. S., and Powell, J. D. (2019). “Glutamine blockade induces divergent metabolic programs to overcome tumor immune evasion.” Science. 366(6468): 1013-1021. https://doi.org/10.1126/science.aav2588.

Lewis, M. T., Kasper, J. D., Bazil, J. N., Frisbee, J. C., and Wiseman, R. W. (2019). “Quantification of Mitochondrial Oxidative Phosphorylation in Metabolic Disease: Application to Type 2 Diabetes.” Int J Mol Sci. 20(21). https://doi.org/10.3390/ijms20215271.

Li, J., Cao, D., Huang, Y., Chen, B., Chen, Z., Wang, R., Dong, Q., Wei, Q., and Liu, L. (2022). “Zinc Intakes and Health Outcomes: An Umbrella Review.” Front Nutr. 9: 798078. https://doi.org/10.3389/fnut.2022.798078.

Li, K., Kaaks, R., Linseisen, J., and Rohrmann, S. (2012). “Vitamin/mineral supplementation and cancer, cardiovascular, and all-cause mortality in a German prospective cohort (EPIC-Heidelberg).” Eur J Nutr. 51(4): 407-413. https://doi.org/10.1007/s00394-011-0224-1.

Li, N., Li, H., Wang, Y., Cao, L., & Zhan, X. (2020). Quantitative proteomics revealed energy metabolism pathway alterations in human epithelial ovarian carcinoma and their regulation by the antiparasite drug ivermectin: data interpretation in the context of 3P medicine. Epma j. 11(4): 661-694. https://doi.org/10.1007/s13167-020-00224-z

Liaghat, M., Yaghoubzad-Maleki, M., Nabi-Afjadi, M., Fathi, Z., Zalpoor, H., Heidari, N., and Bahreini, E. (2024). “A Review of the Potential Role of CoQ10 in the Treatment of Hepatocellular Carcinoma.” Biochem Genet. 62(2): 575-593. https://doi.org/10.1007/s10528-023-10490-x.

Liao, J., Liu, P.P., Hou, G., Shao, J., Yang, J., Liu, K., Lu, W., Wen, S., Hu, Y., and Huang, P. (2017). “Regulation of stem-like cancer cells by glutamine through β-catenin pathway mediated by redox signaling.” Molecular Cancer. 16(1): 51. https://doi.org/10.1186/s12943-017-0623-x.

Lin, L. C., Que, J., Lin, L. K., & Lin, F. C. (2006). Zinc supplementation to improve mucositis and dermatitis in patients after radiotherapy for head-and-neck cancers: a double-blind, randomized study. Int J Radiat Oncol Biol Phys. 65(3): 745-750. https://doi.org/10.1016/j.ijrobp.2006.01.015

Liu, C., Wu, X., Vulugundam, G., Gokulnath, P., Li, G., and Xiao, J. (2023). “Exercise Promotes Tissue Regeneration: Mechanisms Involved and Therapeutic Scope.” Sports Med Open. 9(1): 27. https://doi.org/10.1186/s40798-023-00573-9.

Liu, J., Zhang, K., Cheng, L., Zhu, H., and Xu, T. (2020). “Progress in Understanding the Molecular Mechanisms Underlying the Antitumour Effects of Ivermectin.” Drug Des Devel Ther. 14: 285-296. https://doi.org/10.2147/dddt.s237393.

Liu, X., Ye, N., Xiao, C., Wang, X., Li, S., Deng, Y., Yang, X., Li, Z., and Yang, X. (2021). “Hyperbaric oxygen regulates tumor microenvironment and boosts commercialized nanomedicine delivery for potent eradication of cancer stem-like cells.” Nano Today. 40: 101248. https://doi.org/10.1016/j.nantod.2021.101248

Liu, Y., Sun, Y., Guo, Y., Shi, X., Chen, X., Feng, W., Wu, L. L., Zhang, J., Yu, S., Wang, Y., and Shi, Y. (2023). “An Overview: The Diversified Role of Mitochondria in Cancer Metabolism.” Int J Biol Sci. 19(3): 897-915. https://doi.org/10.7150/ijbs.81609.

Long, Y., Qiu, J., Zhang, B., He, P., Shi, X., He, Q., Chen, Z., Shen, W., Li, Z., and Zhang, X. (2021). “Pharmacological Vitamin C Treatment Impedes the Growth of Endogenous Glutamine-Dependent Cancers by Targeting Glutamine Synthetase.” Front Pharmacol. 12: 671902. https://doi.org/10.3389/fphar.2021.671902.

Lu, H., Cai, L., Mu, L. N., Lu, Q. Y., Zhao, J., Cui, Y., Sul, J. H., Zhou, X. F., Ding, B. G., Elashoff, R. M., Marshall, J., Yu, S. Z., Jiang, Q. W., and Zhang, Z. F. (2006). “Dietary mineral and trace element intake and squamous cell carcinoma of the esophagus in a Chinese population.” Nutr Cancer. 55(1): 63-70. https://doi.org/10.1207/s15327914nc5501_8.

Luo, X., Ng, C., He, J., Yang, M., Luo, X., Herbert, T. P., and Whitehead, J. P. (2022). “Vitamin C protects against hypoxia, inflammation, and ER stress in primary human preadipocytes and adipocytes.” Molecular and Cellular Endocrinology. 556: 111740. https://doi.org/10.1016/j.mce.2022.111740

Lv, H., Wang, C., Fang, T., Li, T., Lv, G., Han, Q.,…Wang, H. (2018). Vitamin C preferentially kills cancer stem cells in hepatocellular carcinoma via SVCT-2. NPJ Precis Oncol. 2(1), 1. https://doi.org/10.1038/s41698-017-0044-8

Lytle, N. K., Barber, A. G. and Reya, T. (2018). “Stem cell fate in cancer growth, progression and therapy resistance.” Nature Reviews Cancer. 18(11): 669-680. https://doi.org/10.1038/s41568-018-0056-x.

Ma, Z., Yang, M., Foda, M. F., Zhang, K., Li, S., Liang, H., Zhao, Y., and Han, H. (2022). “Polarization of Tumor-Associated Macrophages Promoted by Vitamin C-Loaded Liposomes for Cancer Immunotherapy.” ACS Nano. 16(10): 17389-17401. https://doi.org/10.1021/acsnano.2c08446.

Mansoori, S., Fryknäs, M., Alvfors, C., Loskog, A., Larsson, R., and Nygren, P. (2021). “A phase 2a clinical study on the safety and efficacy of individualized dosed mebendazole in patients with advanced gastrointestinal cancer.” Sci Rep. 11(1): 8981. https://doi.org/10.1038/s41598-021-88433-y.

Marigoudar, J. B., Sarkar, D., Yuguda, Y. M., Abutayeh, R. F., Kaur, A., Pati, A., Mitra, D., Ghosh, A., Banerjee, D., Borah, S., Barman, K., Das, B., Khairnar, S. J., Šeherčehajić, E., and Kumar, S. (2022). “Role of vitamin D in targeting cancer and cancer stem cell populations and its therapeutic implications.” Med Oncol. 40(1): 2. https://doi.org/10.1007/s12032-022-01855-0.

Martinez, P., Baghli, I., Gourjon, G., and Seyfried, T. N. (2024). “Mitochondrial-Stem Cell Connection: Providing Additional Explanations for Understanding Cancer.” Metabolites. 14(4). https://doi.org/10.3390/metabo14040229.

Mashhadi, M., Bakhshipour, A., Zakeri, Z. and Ansari-Moghaddam, A. (2016). “Reference Range for Zinc Level in Young Healthy Population in Southeast of Iran.” Health Scope. https://doi.org/10.17795/jhealthscope-18181.

Mathews, E. H., Stander, B. A., Joubert, A. M., and Liebenberg, L. (2014). “Tumor cell culture survival following glucose and glutamine deprivation at typical physiological concentrations.” Nutrition. 30(2): 218-227. https://doi.org/10.1016/j.nut.2013.07.024.

Matta Reddy, A., Iqbal, M., Chopra, H., Urmi, S., Junapudi, S., Bibi, S., Kumar Gupta, S., Nirmala Pangi, V., Singh, I., and Abdel-Daim, M. M. (2022). “Pivotal role of vitamin D in mitochondrial health, cardiac function, and human reproduction.” Excli j. 21: 967-990. https://doi.org/10.17179/excli2022-4935.

McCullough, P. J., Lehrer, D. S., & Amend, J. (2019). Daily oral dosing of vitamin D3 using 5000 TO 50,000 international units a day in long-term hospitalized patients: Insights from a seven year experience. J Steroid Biochem Mol Biol. 189: 228-239. https://doi.org/10.1016/j.jsbmb.2018.12.010

Medjdoub, A., Merzouk, A., Merzouk, H., and Baghli, I. (2016). “Effects of Vitamin C and NADH on in Vitro Proliferative Function of Human Lymphocytes Exposed to Pesticides (Mancozeb and Metribuzin).” Journal of Food Science and Engineering. 6. https://doi.org/10.17265/2159-5828/2016.03.006.

Meidenbauer, J. J., Mukherjee, P., and Seyfried, T. N. (2015). “The glucose ketone index calculator: a simple tool to monitor therapeutic efficacy for metabolic management of brain cancer.” Nutr Metab (Lond). 12: 12. https://doi.org/10.1186/s12986-015-0009-2.

Mihaylova, M. M., Cheng, C. W., Cao, A. Q., Tripathi, S., Mana, M. D., Bauer-Rowe, K. E., Abu-Remaileh, M., Clavain, L., Erdemir, A., Lewis, C. A., Freinkman, E., Dickey, A. S., La Spada, A. R., Huang, Y., Bell, G. W., Deshpande, V., Carmeliet, P., Katajisto, P., Sabatini, D. M., and Yilmaz Ö.H. (2018). “Fasting Activates Fatty Acid Oxidation to Enhance Intestinal Stem Cell Function during Homeostasis and Aging.” Cell Stem Cell. 22(5): 769-778.e764. https://doi.org/10.1016/j.stem.2018.04.001.

Mikirova, N. (2017). “Ascorbic acid and dehydroascorbic acid concentrations in plasma and peripheral blood mononuclear cells after oral liposomal-encapsulated or intravenous ascorbic acid delivery.” J Orthomol Med. 32.

Mocayar Marón, F. J., Ferder, L., Reiter, R. J., and Manucha, W. (2020). “Daily and seasonal mitochondrial protection: Unraveling common possible mechanisms involving vitamin D and melatonin.” J Steroid Biochem Mol Biol. 199: 105595. https://doi.org/10.1016/j.jsbmb.2020.105595.

Moen, I.n and Stuhr, L. E. (2012). “Hyperbaric oxygen therapy and cancer–a review.” Target Oncol. 7(4): 233-242. https://doi.org/10.1007/s11523-012-0233-x.

Moertel, C. G., Fleming, T. R., Creagan, E. T., Rubin, J., O’Connell, M. J., and Ames, M. M. (1985). “High-dose vitamin C versus placebo in the treatment of patients with advanced cancer who have had no prior chemotherapy. A randomized double-blind comparison.” N Engl J Med. 312(3): 137-141. https://doi.org/10.1056/nejm198501173120301.

Mohr, S. B., Gorham, E. D., Kim, J., Hofflich, H., Cuomo, R. E., and Garland, C. F. (2015). “Could vitamin D sufficiency improve the survival of colorectal cancer patients?” J Steroid Biochem Mol Biol. 148: 239-244. https://doi.org/10.1016/j.jsbmb.2014.12.010.

Mohr, S. B., Gorham, E. D., Kim, J., Hofflich, H., and Garland, C. F. (2014). “Meta-analysis of vitamin D sufficiency for improving survival of patients with breast cancer.” Anticancer Res. 34(3): 1163-1166.

Mukherjee, P., Augur, Z. M., Li, M., Hill, C., Greenwood, B., Domin, M. A., Kondakci, G., Narain, N. R., Kiebish, M. A., Bronson, R. T., Arismendi-Morillo, G., Chinopoulos C., and Seyfried, T. N. (2019). “Therapeutic benefit of combining calorie-restricted ketogenic diet and glutamine targeting in late-stage experimental glioblastoma.” Commun Biol. 2: 200. https://doi.org/10.1038/s42003-019-0455-x.

Mukherjee, P., Greenwood, B., Aristizabal-Henao, J., Kiebish, M., and Seyfried, T.N. (2023). Ketogenic diet as a metabolic vehicle for enhancing the therapeutic efficacy of mebendazole and devimistat in preclinical pediatric glioma. bioRxiv. 2023.06.09.544252. https://doi.org/10.1011/2023.06.09.544252

Mukhopadhyay, T., Sasaki, J., Ramesh, R., and Roth, J. A. (2002). “Mebendazole elicits a potent antitumor effect on human cancer cell lines both in vitro and in vivo.” Clin Cancer Res. 8(9): 2963-2969.

Mussa, A., R. A. Mohd Idris, N. Ahmed, S. Ahmad, A. H. Murtadha, T. A. Tengku Din, C. Y. Yean, W. F. Wan Abdul Rahman, N. Mat Lazim, V. Uskoković, K. Hajissa, N. F. Mokhtar, R. Mohamud and R. Hassan (2022) “High-Dose Vitamin C for Cancer Therapy.” Pharmaceuticals. 15(6): 711. https://doi.org/10.3390/ph15060711.

Muñoz, A., and Grant, W. B. (2022). “Vitamin D and Cancer: An Historical Overview of the Epidemiology and Mechanisms.” Nutrients. 14(7). https://doi.org/10.3390/nu14071448.

Nazio, F., Bordi, M., Cianfanelli, V., Locatelli, F., and Cecconi, F. (2019). “Autophagy and cancer stem cells: molecular mechanisms and therapeutic applications.” Cell Death & Differentiation. 26(4): 690-702. https://doi.org/10.1038/s41418-019-0292-y.

Nencioni, A., Caffa, I., Cortellino, S., and Longo, V. D. (2018). “Fasting and cancer: molecular mechanisms and clinical application.” Nat Rev Cancer. 18(11): 707-719. https://doi.org/10.1038/s41568-018-0061-0.

Ngo, B., Van Riper, J. M., Cantley, L. C., and Yun, J. (2019). “Targeting cancer vulnerabilities with high-dose vitamin C.” Nat Rev Cancer. 19(5): 271-282. https://doi.org/10.1038/s41568-019-0135-7.

Nygren, P., and Larsson, R. (2014). “Drug repositioning from bench to bedside: tumour remission by the antihelmintic drug mebendazole in refractory metastatic colon cancer.” Acta Oncol. 53(3): 427-428. https://doi.org/10.3109/0284186x.2013.844359.

Olsen, R. R., Mary-Sinclair, M. N., Yin, Z., & Freeman, K. W. (2015). Antagonizing Bcl-2 family members sensitizes neuroblastoma and Ewing’s sarcoma to an inhibitor of glutamine metabolism. PLoS One. 10(1): e0116998. https://doi.org/10.1371/journal.pone.0116998

Park, D., Lee, J. H., and Yoon, S. P. (2022). “Anti-cancer effects of fenbendazole on 5-fluorouracil-resistant colorectal cancer cells.” Korean J Physiol Pharmacol. 26(5): 377-387. https://doi.org/10.4196/kjpp.2022.26.5.377.

Park, S., Ahn, S., Shin, Y., Yang, Y. and Yeom, C. H. (2018). “Vitamin C in Cancer: A Metabolomics Perspective.” Front Physiol. 9: 762. https://doi.org/10.3389/fphys.2018.00762.

Pastò, A., Bellio, C., Pilotto, G., Ciminale, V., Silic-Benussi, M., Guzzo, G., Rasola, A., Frasson, C., Nardo, G., Zulato, E., Nicoletto, M. O., Manicone, M., Indraccolo, S., and Amadori, A. (2014). “Cancer stem cells from epithelial ovarian cancer patients privilege oxidative phosphorylation, and resist glucose deprivation.” Oncotarget. 5(12): 4305-4319. https://doi.org/10.18632/oncotarget.2010.

Pedersen, P. L. (1978). Tumor mitochondria and the bioenergetics of cancer cells. Prog Exp Tumor Res. 22: 190-274. https://doi.org/10.1159/000401202

Persi, E., Duran-Frigola, M., Damaghi, M., Roush, W. R., Aloy, P., Cleveland, J. L., Gillies, R. J., and Ruppin, E. (2018). “Systems analysis of intracellular pH vulnerabilities for cancer therapy.” Nat Commun. 9(1): 2997. https://doi.org/10.1038/s41467-018-05261-x.

Phillips, M. C. L., Leyden, J., McManus, E. J., Lowyim, D. G., Ziad, F., Moon, B. G., Haji Mohd Yasin, N. A. B., Tan, A., Thotathil, Z., and Jameson, M. B. (2022). “Feasibility and Safety of a Combined Metabolic Strategy in Glioblastoma Multiforme: A Prospective Case Series.” J Oncol. 2022: 4496734. https://doi.org/10.1155/2022/4496734.

Pinto, L. C., Soares, B. M., Pinheiro Jde, J., Riggins, G. J., Assumpção, P. P., Burbano, R. M., & Montenegro, R. C. (2015). The anthelmintic drug mebendazole inhibits growth, migration and invasion in gastric cancer cell model. Toxicol In Vitro. 29(8): 2038-2044. https://doi.org/10.1016/j.tiv.2015.08.007

Poff, A., Koutnik, A. P., Egan, K. M., Sahebjam, S., D’Agostino, D.P., and Kumar, N. B. (2019). “Targeting the Warburg effect for cancer treatment: Ketogenic diets for management of glioma.” Semin Cancer Biol. 56: 135-148. https://doi.org/10.1016/j.semcancer.2017.12.011.

Poff, A. M., Ari, C., Arnold, P., Seyfried, T. N., and D’Agostino, D. P. (2014). “Ketone supplementation decreases tumor cell viability and prolongs survival of mice with metastatic cancer.” Int J Cancer. 135(7): 1711-1720. https://doi.org/10.1002/ijc.28809.

Poff, A. M., Kernagis, D., and D’Agostino, D. P. (2016). “Hyperbaric Environment: Oxygen and Cellular Damage versus Protection.” Compr Physiol. 7(1): 213-234. https://doi.org/10.1002/cphy.c150032.

Poff, A. M., Ward, N., Seyfried, T. N., Arnold, P., and D’Agostino, D. P. (2015). “Non-Toxic Metabolic Management of Metastatic Cancer in VM Mice: Novel Combination of Ketogenic Diet, Ketone Supplementation, and Hyperbaric Oxygen Therapy.” PLoS One. 10(6): e0127407. https://doi.org/10.1371/journal.pone.0127407.

Polireddy, K., Dong, R., Reed, G., Yu, J., Chen, P., Williamson, S.,…Chen, Q. (2017). High Dose Parenteral Ascorbate Inhibited Pancreatic Cancer Growth and Metastasis: Mechanisms and a Phase I/IIa study. Sci Rep. 7(1): 17188. https://doi.org/10.1038/s41598-017-17568-8

Praharaj, P. P., Patro, B. S., and Bhutia, S. K. (2022). “Dysregulation of mitophagy and mitochondrial homeostasis in cancer stem cells: Novel mechanism for anti-cancer stem cell-targeted cancer therapy.” British Journal of Pharmacology. 179(22): 5015-5035. https://doi.org/10.1111/bph.15401

Quigley, M., Rieger, S., Capobianco, E., Wang, Z., Zhao, H., Hewison, M., and Lisse, T. S. (2022). “Vitamin D Modulation of Mitochondrial Oxidative Metabolism and mTOR Enforces Stress Adaptations and Anticancer Responses.” JBMR Plus. 6(1): e10572. https://doi.org/10.1002/jbm4.10572.

Rais, R., Lemberg, K. M., Tenora, L., Arwood, M. L., Pal, A., Alt, J., Wu, Y., Lam, J., Aguilar, J. M. H., Zhao, L., Peters, D. E., Tallon, C., Pandey, R., Thomas, A. G., Dash, R. P., Seiwert, T., Majer, P., Leone, R. D., Powell, J. D., and Slusher, B. S. (2022). “Discovery of DRP-104, a tumor-targeted metabolic inhibitor prodrug.” Sci Adv. 8(46): eabq5925. https://doi.org/10.1126/sciadv.abq5925.

Riordan, H. D., Riordan, N. H., Jackson, J. A., Casciari, J. J., Hunninghake, R., González, M. J., Mora, E. M., Miranda-Massari, J. R., Rosario, N., and Rivera, A. (2004). “Intravenous vitamin C as a chemotherapy agent: a report on clinical cases.” P R Health Sci J. 23(2): 115-118.

Riordan, N., Riordan, H., and Casciari, J. (2000). “Clinical and experimental experiences with intravenous vitamin c.” J Orthomol Med. 15: 13.

Roa, F. J., Peña, E., Gatica, M., Escobar-Acuña, K., Saavedra, P., Maldonado, M., Cuevas, M. E., Moraga-Cid, G., Rivas, C. I., and Muñoz-Montesino, C. (2020). “Therapeutic Use of Vitamin C in Cancer: Physiological Considerations.” Front Pharmacol. 11: 211. https://doi.org/10.3389/fphar.2020.00211.

Satheesh, N. J., Samuel, S. M., and Büsselberg, D. (2020). “Combination Therapy with Vitamin C Could Eradicate Cancer Stem Cells.” Biomolecules. 10(1). https://doi.org/10.3390/biom10010079.

Schmit, J. (2013). In vitro anti-cancer effects of benzimidazoles on the canine osteosarcoma D17 cell line University of Illinois at Urbana-Champaign. http://hdl.handle.net/2142/45401

Sebastian, J. P., Hugh, D. R., Stephen, M. H., Arie, K., Hoffer, L. J., and Mark, L. (2006). “Intravenously administered vitamin C as cancer therapy: three cases.” Canadian Medical Association Journal. 174(7): 937. https://doi.org/10.1503/cmaj.050346.

Seraphin, G., Rieger, S., Hewison, M., Capobianco, E., and Lisse, T. S. (2023). “The impact of vitamin D on cancer: A mini review.” J Steroid Biochem Mol Biol. 231: 106308. https://doi.org/10.1016/j.jsbmb.2023.106308.

Seyfried, T. N., Arismendi-Morillo, G., Mukherjee, P., and Chinopoulos, C. (2020). “On the Origin of ATP Synthesis in Cancer.” iScience. 23(11): 101761. https://doi.org/10.1016/j.isci.2020.101761.

Seyfried, T. N., and Chinopoulos, C. (2021). “Can the Mitochondrial Metabolic Theory Explain Better the Origin and Management of Cancer than Can the Somatic Mutation Theory?” Metabolites. 11(9). https://doi.org/10.3390/metabo11090572.

Seyfried, T. N., Flores, R. E., Poff, A. M., and D’Agostino, D. P. (2014). “Cancer as a metabolic disease: implications for novel therapeutics.” Carcinogenesis. 35(3): 515-527. https://doi.org/10.1093/carcin/bgt480.

Seyfried, T. N., and Huysentruyt, L. C. (2013). “On the origin of cancer metastasis.” Crit Rev Oncog. 18(1-2): 43-73. https://doi.org/10.1615/critrevoncog.v18.i1-2.40.

Seyfried, T. N., Shivane, A. G., Kalamian, M., Maroon, J. C., Mukherjee, P., and Zuccoli, G. (2021). “Ketogenic Metabolic Therapy, Without Chemo or Radiation, for the Long-Term Management of IDH1-Mutant Glioblastoma: An 80-Month Follow-Up Case Report.” Front Nutr. 8: 682243. https://doi.org/10.3389/fnut.2021.682243.

Seyfried, T. N., Yu, G., Maroon, J. C., and D’Agostino, D. P. (2017). “Press-pulse: a novel therapeutic strategy for the metabolic management of cancer.” Nutr Metab (Lond). 14: 19. https://doi.org/10.1186/s12986-017-0178-2.

Sharmeen, S., Skrtic, M., Sukhai, M. A., Hurren, R., Gronda, M., Wang, X.,…Schimmer, A. D. (2010). The antiparasitic agent ivermectin induces chloride-dependent membrane hyperpolarization and cell death in leukemia cells. Blood. 116(18): 3593-3603. https://doi.org/10.1182/blood-2010-01-262675

Sheeley, M. P., Andolino, C., Kiesel, V. A., and Teegarden, D. (2022). “Vitamin D regulation of energy metabolism in cancer.” Br J Pharmacol. 179(12): 2890-2905. https://doi.org/10.1111/bph.15424.

Shelton, L. M., Huysentruyt, L. C., and Seyfried, T. N. (2010). “Glutamine targeting inhibits systemic metastasis in the VM-M3 murine tumor model.” Int J Cancer. 127(10): 2478-2485. https://doi.org/10.1002/ijc.25431.

Sia, J., Szmyd, R., Hau, E., and Gee, H. E. (2020). “Molecular Mechanisms of Radiation-Induced Cancer Cell Death: A Primer.” Front Cell Dev Biol. 8: 41. https://doi.org/10.3389/fcell.2020.00041.

Son, D. S., Lee, E. S., and Adunyah, S. E. (2020). “The Antitumor Potentials of Benzimidazole Anthelmintics as Repurposing Drugs.” Immune Netw. 20(4): e29. https://doi.org/10.4110/in.2020.20.e29.

Song, B., Park, E. Y., Kim, K. J., and Ki, S. H. (2022). “Repurposing of Benzimidazole Anthelmintic Drugs as Cancer Therapeutics.” Cancers (Basel). 14(19). https://doi.org/10.3390/cancers14194601.

Soto, A. M., and Sonnenschein, C. (2011). “The tissue organization field theory of cancer: a testable replacement for the somatic mutation theory.” Bioessays. 33(5): 332-340. https://doi.org/10.1002/bies.201100025.

Sugimoto, R., Lee, L., Tanaka, Y., Morita, Y., Hijioka, M., Hisano, T., and Furukawa, M. (2024). “Zinc Deficiency as a General Feature of Cancer: a Review of the Literature.” Biol Trace Elem Res. 202(5): 1937-1947. https://doi.org/10.1007/s12011-023-03818-6

Suwannasom, N., Kao, I., Pruß, A., Georgieva, R., and Bäumler, H. (2020). “Riboflavin: The Health Benefits of a Forgotten Natural Vitamin.” Int J Mol Sci. 21(3). https://doi.org/10.3390/ijms21030950.

Tamai, Y., Iwasa, M., Eguchi, A., Shigefuku, R., Sugimoto, K., Hasegawa, H., and Takei, Y. (2020). “Serum copper, zinc and metallothionein serve as potential biomarkers for hepatocellular carcinoma.” PLoS One. 15(8): e0237370. https://doi.org/10.1371/journal.pone.0237370.

Tang, M., Hu, X., Wang, Y., Yao, X., Zhang, W., Yu, C., Cheng, F., Li, J., and Fang, Q. (2021). “Ivermectin, a potential anticancer drug derived from an antiparasitic drug.” Pharmacol Res. 163: 105207. https://doi.org/10.1016/j.phrs.2020.105207.

Tiwari, S., Sapkota, N., and Han, Z. (2022). “Effect of fasting on cancer: A narrative review of scientific evidence.” Cancer Sci. 113(10): 3291-3302. https://doi.org/10.1111/cas.15492.

Trump, D. L. (2018). “Calcitriol and cancer therapy: A missed opportunity.” Bone Rep. 9: 110-119. https://doi.org/10.1016/j.bonr.2018.06.002.

van den Boogaard, W. M. C., Komninos, D. S. J., and Vermeij, W. P. (2022). “Chemotherapy Side-Effects: Not All DNA Damage Is Equal.” Cancers (Basel). 14(3). https://doi.org/10.3390/cancers14030627.

Vidal. 2024. Available online: https://www.vidal.fr/medicaments.html (accessed on septembre 05, 2024).

Vuda, M., and Kamath, A. (2016). “Drug induced mitochondrial dysfunction: Mechanisms and adverse clinical consequences.” Mitochondrion. 31: 63-74. https://doi.org/10.1016/j.mito.2016.10.005.

Wan, J., Zhou, J., Fu, L., Li, Y., Zeng, H., Xu, X., Lv, C., and Jin, H. (2021). “Ascorbic Acid Inhibits Liver Cancer Growth and Metastasis in vitro and in vivo, Independent of Stemness Gene Regulation.” Front Pharmacol. 12: 726015. https://doi.org/10.3389/fphar.2021.726015.

Wang, F., He, M. M., Wang, Z. X., Li, S., Jin, Y., Ren, C.,…Xu, R. H. (2019). Phase I study of high-dose ascorbic acid with mFOLFOX6 or FOLFIRI in patients with metastatic colorectal cancer or gastric cancer. BMC Cancer. 19(1): 460. https://doi.org/10.1186/s12885-019-5696-z

Wang, G., Yin, T., & Wang, Y. (2016). In vitro and in vivo assessment of high-dose vitamin C against murine tumors. Exp Ther Med. 12(5): 3058-3062. https://doi.org/10.3892/etm.2016.3707

Wang, J., Xu, Y., Wan, H., & Hu, J. (2018). Antibiotic ivermectin selectively induces apoptosis in chronic myeloid leukemia through inducing mitochondrial dysfunction and oxidative stress. Biochem Biophys Res Commun. 497(1): 241-247. https://doi.org/10.1016/j.bbrc.2018.02.063

Wang, Q., and Zhou, W. (2021). “Roles and molecular mechanisms of physical exercise in cancer prevention and treatment.” J Sport Health Sci. 10(2): 201-210. https://doi.org/10.1016/j.jshs.2020.07.008.

Wang, Y., Sun, Z., Li, A., and Zhang, Y. (2019). “Association between serum zinc levels and lung cancer: a meta-analysis of observational studies.” World J Surg Oncol. 17(1): 78. https://doi.org/10.1186/s12957-019-1617-5.

Ward, N. P., Poff, A. M., Koutnik, A. P., and D’Agostino, D. P. (2017). “Complex I inhibition augments dichloroacetate cytotoxicity through enhancing oxidative stress in VM-M3 glioblastoma cells.” PLoS One. 12(6): e0180061. https://doi.org/10.1371/journal.pone.0180061.

Weber, D. D., Aminazdeh-Gohari, S., and Kofler, B. (2018). Ketogenic diet in cancer therapy. Aging (Albany NY). United States. 10: 164-165.

Weber, D. D., Aminzadeh-Gohari, S., Tulipan, J., Catalano, L., Feichtinger, R. G., and Kofler, B. (2020). “Ketogenic diet in the treatment of cancer – Where do we stand?” Mol Metab. 33: 102-121. https://doi.org/10.1016/j.molmet.2019.06.026.

Wei, Q., Qian, Y., Yu, J., and Wong, C. C. (2020). “Metabolic rewiring in the promotion of cancer metastasis: mechanisms and therapeutic implications.” Oncogene. 39(39): 6139-6156. https://doi.org/10.1038/s41388-020-01432-7.

Woolf, E. C., Syed, N., and Scheck, A. C. (2016). “Tumor Metabolism, the Ketogenic Diet and β-Hydroxybutyrate: Novel Approaches to Adjuvant Brain Tumor Therapy.” Front Mol Neurosci. 9: 122. https://doi.org/10.3389/fnmol.2016.00122.

Wu, S., Zhang, K., Liang, Y., Wei, Y., An, J., Wang, Y., Yang, J., Zhang, H., Zhang, Z., Liu, J., and Shi, J. (2022). “Nano-enabled Tumor Systematic Energy Exhaustion via Zinc (II) Interference Mediated Glycolysis Inhibition and Specific GLUT1 Depletion.” Adv Sci (Weinh). 9(7): e2103534. https://doi.org/10.1002/advs.202103534.

Wu, X., Hu, W., Lu, L., Zhao, Y., Zhou, Y., Xiao, Z., Zhang, L., Zhang, H., Li, X., Li, W., Wang, S., Cho, C. H., Shen, J., and Li, M. (2019). “Repurposing vitamin D for treatment of human malignancies via targeting tumor microenvironment.” Acta Pharm Sin B. 9(2): 203-219. https://doi.org/10.1016/j.apsb.2018.09.002.

Wu, X., Tang, J., and Xie, M. (2015). “Serum and hair zinc levels in breast cancer: a meta-analysis.” Sci Rep. 5: 12249. https://doi.org/10.1038/srep12249.

Xiong, Y., Yong, Z., Xu, C., Deng, Q., Wang, Q., Li, S., Wang, C., Zhang, Z., Yang, X., and Li, Z. (2023). “Hyperbaric Oxygen Activates Enzyme-Driven Cascade Reactions for Cooperative Cancer Therapy and Cancer Stem Cells Elimination.” Adv Sci (Weinh). 10(21): e2301278. https://doi.org/10.1002/advs.202301278.

Xu, C., Yang, H. L., Yang, Y. K., Pan, L., and Chen, H. Y. (2022). “Zinc-finger protein 750 mitigates malignant biological behavior of oral CSC-like cells enriched from parental CAL-27 cells.” Oncol Lett. 23(1): 28. https://doi.org/10.3892/ol.2021.13146.

Xv, F., Chen, J., Duan, L., and Li, S. (2018). “Research progress on the anticancer effects of vitamin K2.” Oncol Lett. 15(6): 8926-8934. https://doi.org/10.3892/ol.2018.8502.

Yang, X., Wang, H., Huang, C., He, X., Xu, W., Luo, Y., and Huang, K. (2017). “Zinc enhances the cellular energy supply to improve cell motility and restore impaired energetic metabolism in a toxic environment induced by OTA.” Scientific Reports. 7(1): 14669. https://doi.org/10.1038/s41598-017-14868-x

Ye, H., Wu, K., Liu, Y., Zhu, Y., Luo, H., and Zou, W. (2022). “Zinc oxide nanoparticle attenuates chemotherapy resistance by inducing cell stemness progression of colorectal cancer via miR-1321/HIF-2α axis.” Arabian Journal of Chemistry. 15(7): 103938. https://doi.org/10.1016/j.arabic.2022.103938

Yokokawa, H., Fukuda, H., Saita, M., Miyagami, T., Takahashi, Y., Hisaoka, T., and Naito, T. (2020). “Serum zinc concentrations and characteristics of zinc deficiency/marginal deficiency among Japanese subjects.” J Gen Fam Med. 21(6): 248-255. https://doi.org/10.1002/jgf2.377.

Yousef, R. G., Elwan, A., Gobaara, I. M. M., Mehany, A. B. M., Eldehna, W. M., El-Metwally, S. A., A Alsfouk, B., Elkaeed, E. B., Metwaly, A. M., and Eissa, I. H. (2022). “Anti-cancer and immunomodulatory evaluation of new nicotinamide derivatives as potential VEGFR-2 inhibitors and apoptosis inducers: in vitro and in silico studies.” J Enzyme Inhib Med Chem. 37(1): 2206-2222. https://doi.org/10.1080/14756366.2022.2110868.

Yu, C., Min, S., Lv, F., Ren, L., Yang, Y., and Chen, L. (2023). “Vitamin C inhibits the growth of colorectal cancer cell HCT116 and reverses the glucose-induced oncogenic effect by downregulating the Warburg effect.” Med Oncol. 40(10): 297. https://doi.org/10.1007/s12032-023-02155-x.

Zeng, X., Dong, X., Xiao, Q., and Yao, J. (2022). “Vitamin C Inhibits Ubiquitination of Glutamate Transporter 1 (GLT-1) in Astrocytes by Downregulating HECTD1.” ACS Chem Neurosci. 13(5): 676-687. https://doi.org/10.1021/acschemneuro.1c00845.

Zhang, C., and Le, A. (2021). “Diabetes and Cancer: The Epidemiological and Metabolic Associations.” Adv Exp Med Biol. 1311: 217-227. https://doi.org/10.1007/978-3-030-65768-0_16.

Zhang, G., Sheng, M., Wang, J., Teng, T., Sun, Y., Yang, Q., and Xu, Z. (2018). “Zinc improves mitochondrial respiratory function and prevents mitochondrial ROS generation at reperfusion by phosphorylating STAT3 at Ser(727).” J Mol Cell Cardiol. 118: 169-182. https://doi.org/10.1016/j.yjmcc.2018.03.019.

Zhang, P., Li, Y., Xu, W., Cheng, J., Zhang, C., Gao, J., Li, Z., Tao, L., and Zhang, Y. (2022). “Immunotoxicity induced by Ivermectin is associated with NF-κB signaling pathway on macrophages.” Chemosphere. 289: 133087. https://doi.org/10.1016/j.chemosphere.2021.133087.

Zheng, X. X., Chen, J. J., Sun, Y. B., Chen, T. Q., Wang, J., and Yu, S. C. (2023). “Mitochondria in cancer stem cells: Achilles heel or hard armor.” Trends Cell Biol. 33(8): 708-727. https://doi.org/10.1016/j.tcb.2023.03.009.

Zhou, H.-M., Zhang, J.-G., Zhang, X., and Li, Q. (2021). “Targeting cancer stem cells for reversing therapy resistance: mechanism, signaling, and prospective agents.” Signal Transduction and Targeted Therapy. 6(1): 62. https://doi.org/10.1038/s41392-020-00430-1.

Zhou, X., Zheng, W., Nagana Gowda, G. A., Raftery, D., Donkin, S. S., Bequette, B., and Teegarden, D. (2016). “1,25-Dihydroxyvitamin D inhibits glutamine metabolism in Harvey-ras transformed MCF10A human breast epithelial cell.” J Steroid Biochem Mol Biol. 163: 147-156. https://doi.org/10.1016/j.jsbmb.2016.04.022.

Zuccoli, G., Marcello, N., Pisanello, A., Servadei, F., Vaccaro, S., Mukherjee, P., and Seyfried, T. N. (2010). “Metabolic management of glioblastoma multiforme using standard therapy together with a restricted ketogenic diet: Case Report.” Nutr Metab (Lond). 7: 33. https://doi.org/10.1186/1743-7075-7-33.

Explore Posts

Join Our Community

Call to Schedule Your Appointment Today! (480) 991-5092.

Blockbuster Cancer Treatment Using Ivermectin Plus High Dose Vitamin C, D and Zinc

Targeting the Mitochondrial-Stem Cell Connection in Cancer Treatment: A Hybrid Orthomolecular Protocol

Explore Posts

Join Our Community

Receive Our Newsletter