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rvwd 12/2024
OPEN ACCESS
protocol page 7 with comments
VOLUME 39 , NUMBER 3
RECEIVED: 17 JUNE 2024 / REVISED : 23 AUGUST 2024
ACCEPTED: 11 SEPTEMBER 2024 / PUBLISHED : 19 SEPTEMBER 2024

EDUCATIONAL ARTICLE

Targeting the Mitochondrial-Stem Cell Connection in Cancer

Treatment: A Hybrid Orthomolecular Protocol

Ilyes Baghli1, William Makis2, Paul E. Marik3, Michael J. Gonzalez4,5,6, 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
1
International Society for Orthomolecular Medicine, Toronto, ON, Canada
2
Alberta Health Services, Cross Cancer Institute, Edmonton, AB, Canada
3
Frontline COVID-19 Critical Care Alliance, Washington, DC, USA
4
University of Puerto Rico, Medical Sciences Campus, School of Public Health, San Juan, PR
5
Universidad Central del Caribe, School of Chiropractic, Bayamon, Puerto Rico
6
EDP University, Naturopathic Sciences Program, Hato Rey, Puerto Rico
7
Sunlight, Nutrition, and Health Research Center, San Francisco, CA, USA
8
Riordan Clinic, 3100 North Hillside, Wichita, KS, USA
9
Akesis Holistic Health, Manila, Philippines
10
Cheng Integrative Health Center, Doctor’s Weight Loss Center, Columbia SC, USA
11
Medical Institute for Nutrition Science and Technology, Riga, LV-1005, Latvia.
12
Association Internationale pour une Médecine Scientifique Indépendante et Bienveillante, Amiens, France
13
Mexican Association of Orthomolecular Nutrition, Mexico City, Mexico
14
Remedy Room Integrative Medicine, New Orleans LA, USA
15
Department of Molecular Pharmacology and Physiology, Laboratory of Metabolic Medicine, Morsani College of Medicine, University
of South Florida, Tampa, FL, USA
16
Association Cancer et Métabolisme, 30000 Nîmes, France.
Correspondence: [email protected]

Citation: Baghli I, et al. (2024) Targeting the Mitochondrial-Stem Cell Connection in Cancer Treatment: A Hybrid Orthomolecular
Protocol. J Orthomol Med. 39.3
MSCC = Mitochondrial Stem Cell Connection
CSC = Cancer Stem Cell
OxPhos = core mitochondrial process that can go awry
ABSTRACT
consisting of orthomolecules, drugs, and additional thera-
The mitochondrial-stem cell connection (MSCC) theory sug-
pies. The aim of this hybrid orthomolecular protocol is to
gests that cancer originates from chronic oxidative
achieve additive and synergistic effects to enhance OxPhos,
phosphorylation (OxPhos) insufficiency in stem cells. This
inhibit the primary fuels of cancer cells (glucose and glu-
OxPhos insufficiency leads to the formation of cancer stem
tamine), target CSCs and metastasis. Thus, numerous
cells (CSCs) and abnormal energy metabolism, ultimately
experiments suggest that targeting MSCC could be a poten-
resulting in malignancy. This concept integrates two well-es-
tial therapeutic approach for cancer treatment.
tablished theories: the cancer stem cell theory and the
metabolic theory. Drawing on insights from molecular biol- Keywords: cancer metabolism; mitochondria; oxidative
ogy, pharmacology, and clinical studies, this manuscript phosphorylation; cancer stem cells; glucose; glutamine;
introduces a hybrid orthomolecular protocol targeting the orthomolecules; repurposed drugs; diet; lifestyle interventions
MSCC. The protocol includes 7 therapeutic recommendations,

© 2024 International Society for Orthomolecular Medicine ISSN 0317-0209

Targeting the Mitochondrial-Stem Cell Connection in Cancer Treatment
SMT = Somatic Mutation Theory = old genetic theory
INTRODUCTION Key Points of the MSCC:
Many theories exist regarding the origin of cancer, namely • An alteration of OxPhos may initiate tumorigenesis in
the metabolic theory (Seyfried & Chinopoulos, 2021), the one or more normal stem cells, leading to the forma-
somatic mutation theory (SMT) (Hanahan & Weinberg, tion of CSCs (Martinez, et al., 2024).
2000), the cancer stem cell theory (Capp, 2019), and the
• The degree of malignancy could be directly corre-
tissue organization theory (Soto & Sonnenschein, 2011). In
lated with significantly lower mitochondria and lower
a recently published study, a new concept was introduced
total respiratory capacity in tumor cells (Elliott, et al.,
the mitochondrial-stem cell connection (MSCC) (Martinez,
2012; Pedersen, 1978; Seyfried, et al. 2020).
et al., 2024). This concept combines the cancer stem cell
theory and the metabolic theory. The MSCC theory sug- • In order to grow and survive, cancer cells require the
gests that cancer arises from impaired oxidative primary fuels glucose and glutamine to compensate
phosphorylation (OxPhos) in one or more stem cells, for OxPhos insufficiency. The respiratory impairment
potentially leading to the formation of cancer stem cells induces overexpression of oncogenes and inactiva-
(CSCs) and, consequently, tumorigenesis. This connection tion of tumor-suppressor genes, which contribute to
between CSCs and mitochondria appears to be crucial at abnormal energy metabolism in cancer. To date, no
all stages of cancer (Martinez, et al., 2024). The MSCC aligns evidence has demonstrated the growth of any tumor
with the metabolic theory of cancer but specifically cells, including CSCs, occurs with the deprivation of
focuses on the crucial role of CSCs in every stage of the dis- fermentable fuels (glucose, pyruvate, or glutamine)
ease. However, the MSCC differs from the CSCs theory, (Lee, et al., 2024; Liao, et al., 2017; Holm, et al., 1995;
which typically presents cancer as a genetic disease. Thus, Mathews, et al., 2014; Pastò, et al., 2014).
many standard cancer therapies are based on the SMT and
• The tumor microenvironment (a consequence of
generally target the DNA of cancer cells (van den
mitochondrial impairment) is characterized by low
Boogaard, et al., 2022; Sia, et al., 2020). These therapies do
pH (acidic), hypoxia, entropy, pressure and deforma-
not restore OxPhos and sometimes even alter it (Averbeck
tion, increased temperature, stroma, altered rotation
& Rodriguez-Lafrasse, 2021; Gorini, et al., 2018). Further-
of cytoplasmic water, and damped bioelectricity or
more, standard therapies only target bulk cells but cannot
electromagnetic field (Martinez, et al., 2024).
target CSCs (Lytle, et al., 2018), whereas it is CSCs that have
the strongest tumorigenic potential (Adams & Strasser, • Metastasis remains the leading cause of cancer mor-
2008) and are involved in metastasis. This information tality. According to MSCC, it occurs due to fusion
could partially explain the outcomes observed with the hybridization between CSCs and macrophages (Mar-
new anticancer therapies. Indeed, Ladanie et al. showed tinez, et al., 2024; Seyfried & Huysentruyt, 2013).
that over the past fifteen years, new therapies have led to
These principles are applicable to all types of cancer.
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). ORTHOMOLECULAR MEDICINE FOR TARGETING
THE MSCC
Thus, after reviewing the literature on various therapies
capable of targeting the MSCC, we selected, based on in Vitamin C
vitro and in vivo studies, several orthomolecules, drugs, The anti-cancer properties of vitamin C have been known
and additional therapies that have demonstrated an ability for over 50 years (Mussa, et al., 2022). Vitamin C demon-
to enhance OxPhos, reduce fermentable fuels, and target strates cytotoxic effects on cancer cells both in vitro and in
CSCs and metastasis. Furthermore, when supported by vivo (Fan, et al., 2023). In vitro, vitamin C alone is more
scientific literature, we included case studies of cures using effective than chemotherapy (cisplatin) alone at inducing
monotherapy in humans. From this combination, we apoptosis in colon cancer cells (Wang, et al., 2016). In vivo,
developed a hybrid orthomolecular protocol, which is pro- vitamin C alone significantly reduces tumor weight and
posed as a new therapeutic strategy for cancer. the number of metastases in pancreatic cancer, whereas
standard chemotherapy (gemcitabine) alone, commonly

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Targeting the Mitochondrial-Stem Cell Connection in Cancer Treatment

used for pancreatic cancer, increases tumor weight and the inhibition can reverse the phenotype of M2 macrophages
number of metastases (Polireddy, et al., 2017). In vivo hep- and promote the polarization of M1 macrophages. It will
atocellular carcinoma, vitamin C alone reduces CSCs and reduce intracellular glutamine and the absorption of glu-
tumor volume, whereas conventional therapy (cisplatin) tamine will be channeled, which will eliminate metastases
alone reduces tumor volume (to a lesser extent than vita- (Wei, et al., 2020). Thus explaining the glutamine depen-
min C) but increases CSCs (Lv, et al., 2018). Vitamin C can dence observed in advanced cancers (Seyfried, et al., 2020)
directly infiltrate into the tumor intracellular environment, and confirming the role of vitamin C on metastatic cancers.
reduce oxidative stress, target the mitochondria of cancer
The pioneers of intravenous vitamin C cancer treatment,
cells, and induce cancer cell death, including metastases
Cameron and Pauling, observed improved survival times
(Roa, et al., 2020; Wan, et al., 2021). The alkaline intracellular
for many cancers (lung, stomach, colon, breast, kidney,
environment of cancer cells, with a pH between 7.1 and
rectum, and bladder). They observed survival times multi-
7.7, maximizes the proliferation of cancer cells (Cardone, et
plied by 55 after 1 year, in terminal cancer patients treated
al., 2005; Gillies, et al., 2002). Vitamin C, through its acidic
with intravenous injections of ascorbate: 22% in the
pH, could deactivate the environmental adaptations,
treated group and 0.4% in the control group in patients
having anti-cancer effects by compromising the growth of
considered to be incurable following standard treatment.
tumor cells and inhibiting tumor progression (Persi, et al.,
Their intervention consisted of an intravenous injection of
2018). It can increase ATP production by increasing mito-
10 g/day for approximately 10 days and orally thereafter
chondrial electron flux, thereby restoring cellular
(Cameron & Pauling, 1978). The Mayo Clinic attempted to
respiration and apoptosis function (Gonzalez, et al., 2010;
reproduce these results, but intravenous vitamin C was
Gonzalez, et al., 2023).
replaced by oral vitamin C and the results were therefore
Vitamin C can target and eradicate CSCs (Bonuccelli, et al., unsurprisingly not reproduced (Moertel, et al., 1985). The
2017; Lee, 2023; Satheesh, et al., 2020), and protect against plasma concentrations, and therefore the effects of vita-
hypoxia and inflammation (Luo, et al., 2022). It can induce min C, are much lower with oral supplementation
apoptosis in drug-resistant cancer cells, and inhibit uncon- (Mikirova, 2017). Several case studies have been published
trolled proliferation of cancer cells and metastatic spread by the Riordan Clinic team and collaborators, reporting
(Butt, et al., 2020). Vitamin C can also cause a polarization cases of tumor regression in patients who received intra-
of M2 macrophages into M1 macrophages. This could be venous vitamin C (Riordan, et al., 2000; Riordan, et al., 2004;
particularly relevant for inhibiting metastatic spread Sebastian, et al., 2006). Additionally, Li and colleagues
because M2 macrophages are implicated in metastases showed that when taken regularly, antioxidant vitamins
(Ma, et al., 2022). High pharmacological intravenous doses (vitamins A, C and E) could reduce cancer mortality (Li, et
of vitamin C have been shown to kill cancer cells but not al., 2012). However, the antioxidant action of vitamin C
normal cells (Chen, et al., 2005; Chen, et al., 2008; Ngo, et should primarily be used in cancer prevention (Deruelle &
al., 2019). For example, high doses of intravenous vitamin Baron, 2008), as antioxidants can sometimes promote
C may induce apoptotic cell death in tumor cell lines tumor growth (Long, et al., 2021).
through a pro-oxidant mechanism (Gonzalez, et al., 2010;
Vitamin D
Kc, et al., 2005; Mussa, et al., 2022).
Vitamin D has shown anti-cancer effects in vitro and in vivo
In normal cells, vitamin C enters mitochondria in its oxi-
for almost all cancer types (Chakraborti, 2011; Seraphin, et
dized form via glucose receptors (Glut1) and protects
al., 2023). Like vitamin C, it targets the mitochondria by
mitochondria from oxidative injury (Kc, et al., 2005). Thus,
improving metabolism and regulating mitochondrial res-
vitamin C can directly compete with glucose for cellular
piration (Matta Reddy, et al., 2022; Quigley, et al., 2022).
entry by glucose receptor.
Vitamin D can also target CSCs and metastases
Glycolysis and glutaminolysis have a major role in the (Marigoudar, et al., 2022; Wu, et al., 2019), and inhibit gly-
metabolism of cancer cells. Vitamin C has the ability to colysis and glutaminolysis pathways (Sheeley, et al., 2022;
inhibit glycolysis (Aguilera, et al., 2016; Park, et al., 2018; Yu, Zhou, et al., 2016). It has been observed that daily vitamin
et al., 2023) and glutamate synthesis (Zeng, et al., 2022). It D supplementation can reduce total cancer mortality, but
can specifically limit glutamine synthesis by inhibiting glu- this has not been observed for infrequent large bolus
tamine synthetase (GS), leading to a decrease in the level doses (Keum, et al., 2022). Cancer patients are often defi-
of glutathione and an increase in reactive oxygen species cient in vitamin D and they can benefit from effective
(ROS) thus resulting in cell death (Long, et al., 2021). GS therapy with minimal risk (Hohaus, et al., 2018), including
plays a key role in macrophages and thus in metastases. GS intravenously (Dressler, et al., 1995; Fakih, et al., 2007;

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Targeting the Mitochondrial-Stem Cell Connection in Cancer Treatment

Trump, 2018). One case report details an elderly patient There are a total of 151 publications confirming the link
with advanced pancreatic cancer who was unable to between zinc deficiency and malignancy (Sugimoto, et al.,
undergo chemotherapy, radiation, or surgery. Instead, the 2024). Zinc deficiency is implicated in many cancers,
patient received a daily dose of 50,000 IU of vitamin D3 for including oesophageal, liver, lung, breast, colon and others
9 months and experienced an unexpectedly prolonged (Lu, et al., 2006; Tamai, et al., 2020; Wang, Y., et al., 2019; Wu,
period of disease-free progression, far exceeding what et al., 2015). Zinc shows toxicity toward cancer cells with-
would have been expected with conventional chemother- out showing any side effects toward healthy cells and
apy (Cannon, et al., 2016). deficiency negatively correlates with survival rates (Gel-
bard, 2022; Sugimoto, et al., 2024). Similar to vitamin C, zinc
Chandler et al. showed a preventive effect of vitamin D
may have a specific pro-oxidant effect on cancer cells (Aljo-
supplementation in patients with a normal body mass
har, et al., 2022).
index (BMI), demonstrating a 37% reduction in the inci-
dence 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 Vita- POTENTIAL DRUGS FOR TARGETING THE MSCC
min D group and 68 people in the placebo group). The Several pharmaceutical agents can primarily target
dose utilized was 2000 IU/day, which is the recommended genetic pathways associated with CSCs, including Vismod-
daily intake for a healthy individual (Chandler, et al., 2020). egib, Glasdegib, MK-0752, OMP-54F28, and Selinexor
A recent randomized controlled trial on vitamin D supple- (Zhou, et al., 2021). Other pharmaceutical agents have
mentation (2000 IU/d vitamin D3 versus placebo) found been proposed to target mitochondria, such as Metformin
that gastrointestinal cancer patients who were p53 for OxPhos (Ward, et al., 2017; Zheng, et al., 2023) Doxycy-
immunoreactive experienced a significant reduction in cline, Tigecycline, and Bedaquiline for mitochondrial
relapse or death associated with vitamin D supplementa- biogenesis; Mdivi-1 drug in mitochondrial dynamics; and
tion over nearly six years of follow-up (Kanno, et al., 2023). 188Re-liposome and the inhibitor liensinine to block
Meta-analyses of observational studies for at least 12 mitophagy (Jagust, et al., 2019; Praharaj, et al., 2022). Most
different cancer types reported the inverse correlations of of the time, these agents do not restore mitochondrial
serum 25-hydroxyvitamin D [25(OH)D] and cancer inci- homeostasis (Liu, Y., et al., 2023), as their specific actions
dence (Muñoz & Grant, 2022). alter or only partly restore dysfunction. The alteration of
Zinc mitochondrial function with pharmaceutical agents must
be considered with caution, as it can be very dangerous for
Zinc supplementation has been recommended as a possi- healthy cells (Vuda & Kamath, 2016).
ble adjunctive treatment for cancer. (Costello & Franklin,
2017; Hoppe, et al., 2021) Zinc specifically protects mito-
chondria from damage by reactive oxygen species that are REPURPOSED ( OFF - LABEL) DRUGS FOR TARGETING
generated as by-products of mitochondrial respiration
THE MSCC
(Zhang, et al., 2018). It has been shown that zinc supple-
mentation induces mitochondrial pyruvate transport, Ivermectin
oxidative phosphorylation, and ATP production in both
An anti-parasitic derived from a bacteria called Strepto-
normal and toxic-induced oxidative stress in vitro (Yang, et
myces avermitilis, Ivermectin has anti-cancer properties
al., 2017). In human ovarian cancer cells, zinc induces
and induces autophagy and apoptosis of cancer cells (Liu,
degradation of mitochondria, and restores apoptosis,
et al., 2020). Ivermectin has shown a significant impact on
especially if introduced together with zinc ionophores
various cancer cell lines (Juarez, et al., 2020), inducing
(Chen, et al., 2020). Zinc can suppress cancer stem cell-like
apoptosis in cancer cells in vivo (Sharmeen, et al., 2010)
properties of oral cancer and breast cancer cells in vitro
and significantly reducing tumor volume compared to a
(Chu, et al., 2023; Xu, et al., 2022), reduce the expression of
control (Juarez, et al., 2020). It induces apoptosis in cancer
markers of cancer cell stemness, and enhance sensitivity to
cells through mitochondrial mediation (Juarez, et al., 2018;
chemotherapy in colorectal cancer cells (Ye, et al., 2022).
Tang, et al., 2021). Ivermectin can target and regulate the
Excess zinc can irreversibly block energy production of
pyruvate kinase muscle isoforms at the last step of glycoly-
cancer cells, cause NAD+ loss, and inhibit cellular glycolysis
sis (Li, et al., 2020). It can inhibit glycolysis inducing
(Wu, et al., 2022).
autophagy (Feng, et al., 2022), and have a selective a pro-
oxidant effect on cancer cells (Wang, et al., 2018). It can

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Targeting the Mitochondrial-Stem Cell Connection in Cancer Treatment

also target CSCs and metastases (Dominguez-Gomez, et al., 1993). Patients receiving 1500 mg/day of Mebendazole
al., 2018; Jiang, et al., 2022) and macrophages (Zhang, et for gliomas were also noted to be without toxicity from the
al., 2022). In vitro, Ivermectin is more effective at inhibiting drug (Chai, et al., 2021). Patients with treatment refractory
CSCs in breast cancer cells compared to chemotherapy gastrointestinal cancer participating in a phase 2 study
(paclitaxel) (Dominguez-Gomez, et al., 2018). In vivo, Iver- using individualized doses of Mebendazole, up to 4 g/day,
mectin alone is more effective than standard chemo- experienced no severe adverse effects (Mansoori, et al.,
therapy (gemcitabine) alone at reducing tumor weight 2021). A case of near-complete remission was reported in
and volume in pancreatic cancer (Lee, et al., 2022). Iver- a patient with metastatic colon cancer after taking Meben-
mectin is a very safe drug. In healthy volunteers, the single dazole, following a failure of chemotherapeutic agents
dose was increased to 2 mg/Kg, and no serious adverse including Capecitabine, Oxaliplatin, Bevacizumab,
reactions were found (Guzzo, et al., 2002). Demonstrated in Capecitabine and Irinotecan (Nygren & Larsson, 2014). In
another study, cancer patients who took Ivermectin at five another case report, a 48-year-old man with adrenocortical
times the standard dose (up to 1mg/kg) daily for up to 180 carcinoma had disease progression with all systemic thera-
consecutive days had no serious adverse effects (de Castro, pies. He was prescribed Mebendazole 100mg twice daily,
et al., 2020). In cases successfully treated with a total or par- as a single agent. His metastases initially regressed and
tial combination of Ivermectin, dichloroacetate, and subsequently remained stable. While receiving Mebenda-
Omeprazole (plus Tamoxifen), Ivermectin inhibited tumor zole as a sole treatment for 19 months, his disease
growth through mitochondrial dysfunction and led to remained stable. He did not experience any clinically sig-
apoptosis (Ishiguro, et al., 2022). nificant adverse effects, and his quality of life was
satisfactory (Dobrosotskaya, et al., 2011). Similar results
Benzimidazoles
have been observed with Fenbendazole, three patients
Another family of drugs called Benzimidazoles holds with stage IV cancer (genitourinary malignancies) were
promising anticancer capabilities including Fenbendazole treated at a dose of 1,000 mg three times weekly for several
and Mebendazole. Mebendazole and Fenbendazole are months and experienced complete remission of the dis-
very structurally similar and generally just as effective in ease (Chiang, et al., 2021). Two of the three patients had
cancer (Bai, et al., 2011; Florio, et al., 2019; Schmit, 2013), in experienced progression of metastatic disease despite sev-
both in vitro and in vivo models (Song, et al., 2022). How- eral lines of treatment before starting Fenbendazole.
ever, only Mebendazole is FDA approved for use in humans
DON (6-diazo-5-oxo-L-norleucine)
(Impax, 2016). Benzimidazoles have anticancer effects
through microtubule polymerization, induction of apopto- DON is a glutamine-specific antagonist more potent than
sis, cell cycle arrest (G2/M), anti-angiogenesis, blocking Benzimidazoles. DON has potent antitumor activity in vitro
glucose (Son, et al., 2020) and glutamine pathways and in vivo (Olsen, et al., 2015). It specifically targets glu-
(Mukherjee, et al., 2023). Apoptosis is induced by mito- tamine and also affects glucose uptake (Leone, et al., 2019).
chondrial injury and mediated by p53 expression DON can specifically induce apoptosis in CSCs (Jariyal,
(Mukhopadhyay, et al., 2002; Park, et al., 2022). Benzimida- et al., 2021), and target metastases (Shelton, et al., 2010).
zoles also target CSCs and metastases (Son, et al., 2020; Low daily doses of DON are without toxicity (Lemberg, et
Song, et al., 2022) and, thus, the chemoresistant (cisplatin) al., 2018).
cancer cells (Huang, et al., 2021). Mebendazole was more
potent against gastric cancer cell lines than other well-
known chemotherapeutic drugs (5-fluorouracil, oxali- DIETARY INTERVENTIONS FOR TARGETING THE MSCC
platin, gemcitabine, irinotecan, paclitaxel, cisplatin,
etoposide and doxorubicin) in vitro (Pinto, et al., 2015). Fasting
Whereas Mebendazole leads to significantly prolonged Fasting induces an improvement in mitochondrial
survival compared to standard chemotherapy (temozolo- activity through the increase of OxPhos, autophagy,
mide) for glioblastoma multiforme in vivo (Bai, et al., 2011). and the inhibition of glycolysis and glutaminolysis
Mebendazole is established as a safe drug. In pediatric (Bianchi, et al., 2015; Nencioni, et al., 2018; Tiwari, et al.,
patients with hydatid disease, long-term Mebendazole 2022). Fasting can train the regeneration of “normal”
treatment (50 mg/kg daily for 9–18 months) was demon- stem cells (Mihaylova, et al., 2018), but it can also alter
strated to be without significant side effects (Göçmen, et CSCs through autophagy (Nazio, et al., 2019). Inhibi-

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Targeting the Mitochondrial-Stem Cell Connection in Cancer Treatment

tion or deprivation of glucose leads to the death of ADDITIONAL THERAPEUTIC CONSIDERATIONS

CSCs (De Francesco, et al., 2018). In vivo, fasting has
anticancer effects and enhances the activity of drugs Press-Pulse Therapy
with which it is combined (Nencioni, et al., 2018). Press-Pulse therapy offers two-axis therapy. The “Press”
Taking into account the molecular mechanisms of axis, which consists of following a ketogenic diet associ-
cancer growth, researchers have affirmed that “… pre- ated with stress management. And a Pulse axis, which
scribing fasting as an anticancer drug may not be far combines inhibition of glycolysis by 2-deoxyglucose (2-
away if large randomised clinical trials consolidate its DG), inhibition of glutaminolysis by DON (6-diazo-5-oxo-L-
safety and efficacy” (Deligiorgi, et al., 2020). norleucine), and hyperbaric oxygen therapy (HBOT) to
Ketogenic Diet and Ketone Metabolic Therapy (KMT) reverse hypoxia and induce cancer-specific oxidative stress
(Seyfried, et al. 2017). The metabolic theory underlying the
Therapeutic ketosis given as a ketogenic diet or ketone Press-Pulse therapy is the closest to the proposed MSCC
metabolic therapy (KMT) inhibits cancer stem cell growth, theory.
restores apoptosis (Ji, et al., 2020), and increases cellular
respiration (Greco, et al., 2016). The ketogenic diet exhibits Physical Activity
antitumor effects both in vitro and in vivo, primarily by Diabetes and obesity are risk factors for many cancers
inhibiting the glycolysis pathway in various types of cancer (Grant, 2024), probably through the alteration of OxPhos
(Weber, et al., 2018; Weber, et al., 2020), and its efficacy has (Lewis, et al., 2019), promote CSCs (Hillers-Ziemer, et al.,
been demonstrated in humans with glioblastoma muti- 2020) and the increase of the Warburg effect (Zhang & Le,
forme (Elsakka, et al., 2018; Zuccoli, et al., 2010). The 2021). Thus, physical activity may confer a protective role.
maximum therapeutic benefits of DON and Mebendazole Endurance exercises increase the volume of mitochondria,
occurred only when the drugs were administered together which improves mitochondrial respiration (Baldwin, et al.,
with a ketogenic diet (Mukherjee, et al., 2019; Mukherjee, 1972; Jacobs & Lundby, 2013) and its protective effects on
et al., 2023). Moreover, the association between a keto- healthy cells (Kolodziej & O’Halloran, 2021). Exercise also
genic diet and DON reduces DON toxicity (Mukherjee, et decreases glycolytic activity (Gibb, et al., 2017). ATP pro-
al., 2019). A ketogenic diet or fasting could inhibit the fuels duction and mitochondrial respiration are highest during
necessary for cancer cells (glucose and glutamine) while regular low to moderate intensity training (Flockhart, et al.,
also increasing the activity of OxPhos (Bianchi, et al., 2015). 2021). Physical activity supports tissue regeneration, in
A case study reported the survival of a patient with grade part with stem cells (Liu, C., et al., 2023). Specifically con-
IV glioblastoma living more than 6 years after diagnosis, cerning cancer cells, physical activity inhibits their
treated with surgical reduction and a ketogenic diet under proliferation and induces apoptosis (Wang & Zhou, 2021).
therapeutic ketosis without chemoradiotherapy (Seyfried,
Shivane, et al., 2021). Foster analyzed 200 cases of sponta- Hyperbaric Oxygen therapy (HBOT)
neous cancer regression, and showed that 87% made a Hypoxia is a critical characteristic of malignant tumors and
major change in diet, primarily vegetarian in nature, 55% involves enhanced cell survival, angiogenesis, glycolysis
used some form of detoxification, and 65% used nutri- and glutaminolysis metabolism, and metastasis. There is
tional supplements (Foster, 1988). The goal with the evidence that implies oxygen is a drug, dependent upon
ketogenic diet and ketone metabolic therapy is to simulta- the dose (Poff, et al., 2016) and that HBOT has tumor-in-
neously restrict the glycolysis and glutaminolysis hibitory effects, especially when combined with KMT
pathways while at the same time transition the body into a (Seyfried, et al., 2014). HBOT exhibits potent antitumor
state of ketosis to target the cancer cells – both CSCs and activity both in vitro and in vivo, whether used alone or in
non-cancer stem cells. In addition to metabolic ketosis, combination (Moen & Stuhr, 2012). Tumor cells may adapt
ketone supplementation studies have demonstrated that to ischemic and low nutrient microenvironments by three
ketones independently enhance mitochondrial function main adaptations: the angiogenic switch, deregulation of
(Woolf, et al., 2016; Seyfried, et al., 2017) and suppress apoptosis, and the metabolism shift (Daruwalla &
tumor growth by targeting metastasis and most hallmarks Christophi, 2006). HBOT can target CSCs and metastases
of cancer (Poff, et al., 2014; Poff, et al., 2019). (Liu, et al., 2021; Xiong, et al., 2023) and increase OxPhos

6 | Journal of Orthomolecular Medicine, Volume 39, Number 3, 2024

 Targeting the Mitochondrial-Stem Cell Connection in Cancer Treatment

(Hadanny, et al., 2022). KMT is synergistic with HBOT and 4 Ivermectin

elicits a potent synergistic effect on suppressing tumor 150# = 70 kg = 35 mg
Low-grade cancers:
growth and metastatic spread in pre-clinical models of
Dose of 0.5mg/kg, 3x per week (Guzzo, et al., 2002).
metastatic cancer and human case reports (Elsakka, et al.,
2018; Poff, et al., 2015; Poff, et al., 2019). Intermediate-grade cancers:
Dose of 1mg/kg, 3x per week (Guzzo, et al., 2002).
High-grade cancers:
PROPOSED HYBRID ORTHOMOLECULAR PROTOCOL Dose from 1 mg/kg/day (de Castro, et al., 2020) to 2 mg/
Based on our review of the scientific literature, the follow- kg/day (Guzzo, et al., 2002). 70 x 2 = 140 mg/day
ing protocol combining orthomolecules, drugs and All these doses have been established as tolerable for
additional therapies for targeting the MSCC in cancer treat- humans (Guzzo, et al., 2002).
ment is proposed:

1.5 x 70 kg = 135 gm! 5 Benzimidazoles and DON

1 Intravenous Vitamin C
Low-grade cancers:
Intermediate- and high-grade cancers: Mebendazole: Dose of 200 mg/day (Dobrosotskaya,
Dose of 1.5g/kg/day, 2-3x per week (Fan, et al., 2023). et al., 2011).
Established as a non-toxic dose for cancer patients
(Wang, F., et al., 2019). Intermediate-grade cancers:
Mebendazole: Dose of 400 mg/day (Chai, et al., 2021).

2 Oral Vitamin D High-grade cancers:

Mebendazole dose of 1,500 mg/day (Son, et al., 2020) or
All cancer grades: Fenbendazole 1,000 mg 3x per week (Chiang, et al.,
Dose of 50,000 IU/day for patients with a blood level ≤ 2021).
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 All these doses have been established as tolerable for
check dose (Cannon, et al., 2016; Ghanaati, et al., 2020; McCul- humans (Chai, et al., 2021; Chiang, et al., 2021; Son, et al.,
lead lough, et al., 2019). 2020). Benzimidazoles can be replaced or combined
(Pb) with DON, administered without toxicity; intravenously
It is necessary to reach a blood level of 80 ng/mL of vita- or intramuscularly: 0.2 to 0.6 mg/kg once daily; or orally:
levels min D (25-hydroxyvitamine D (25(OH) D) (Kennel, et al., 0.2 to 1.1 mg/kg once daily (Lemberg, et al., 2018; Rais, et
2010; Mohr, et al., 2014; Mohr, et al., 2015). This level is al., 2022). Benzimidazole are much easier to obtain than
non-toxic (Holick, et al., 2011). Once this level is reached DON. However, for metastatic cancers, which rely heavily
it must be maintained with a reduced daily dosage of ≈ on glutamine (Seyfried, et al., 2020), a combination of
2000 IU/day (Ekwaru, et al., 2014). The vitamin D blood DON and Benzimidazoles should be considered
concentration should be measured every two weeks for (Mukherjee, et al., 2023).
high doses and monthly for lower doses.
6 Dietary Interventions
3 Zinc
All cancer grades:
All cancer grades: Ketogenic diet (low carbohydrate-high fat diet, 900 to
Dose of 1 mg/kg/day is established as a non-toxic dose 1500 kcal/day) (Weber, et al., 2020).
for cancer patients (Hoppe, et al., 2021; Lin, et al., 2006).
Ketone metabolic therapy consists of approximately 60-
The reference range for serum zinc concentration is 80 to 80% fat, 15-25% protein and 5-10% fibrous carbohy-
120 μg/dL (Mashhadi, et al., 2016; Yokokawa, et al., 2020). drates. Adequate hydration and single-ingredient whole
Once this level is reached it must be maintained with a food ketogenic meals are necessary to achieve a glucose
reduced daily dosage of 5mg/day (Li, et al., 2022). The ketone index (GKI) score of 2.0 or below (Meidenbauer,
zinc blood concentration should be measured monthly. et al., 2015; Seyfried, Shivane, et al., 2021). GKI should be
use RBC Zn and TEE Zn as additional guides;
serum levels not great!
7 | Journal of Orthomolecular Medicine, Volume 39, Number 3, 2024
 Targeting the Mitochondrial-Stem Cell Connection in Cancer Treatment

measured 2–3 hours postprandial, twice a day if possible chondria, offering protective action for these cells. How-
(Meidenbauer, et al., 2015; Seyfried, Shivane, et al., 2021). ever, in cancer cells, both CSCs and non-CSCs, the pro-
Intermediate- and high-grade cancers: oxidant effect of the combination induces apoptosis.
The ketogenic diet should be coupled with a water fast Additionally, this protocol specifically targets fermentable
for 3 to 7 consecutive days in advanced cancers (Phillips, fuels, CSCs and macrophages, and thus metastases. In
et al., 2022; Arora, et al., 2023). The water fast should be brief, the key points of the MSCC. Therefore, comparative
repeated several times (≈ every 3-4 weeks) throughout studies need to be conducted in both animals and humans
the treatment (Nencioni, et al., 2018), but fasting needs to to evaluate the effectiveness and safety of this hybrid
be undertaken cautiously in individuals using certain protocol against standard therapies.
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, CONCLUSION
juices, nut bars, and herbal teas) can be used (Nencioni,
et al., 2018). The mitochondrial-stem cell connection could be a key
element in the therapeutic approach to cancer. In light of
7 Additional Therapeutics current knowledge, we have selected and propose the use
All cancer grades: of specific orthomolecules, drugs and other therapies for
Moderate physical activity, 3x per week. Increased heart their potential to revive cellular OxPhos activity, and target
and respiratory rate for a period of 45 to 75 minutes (Bull, CSCs, glycolysis and glutaminolysis. These are also aimed
et al., 2020) with activities such as cycling, running, at addressing metastases created by fusion hybridization
swimming, etc. between cancer stem cells and macrophages. Numerous
experiments in cells, animals, and humans support the role
Intermediate- and high-grade cancers or individuals of targeting the MSCC in both the prevention and treat-
who are unable to engage in physical activity: ment of cancer.
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). CONFLICTS OF INTEREST
The protocol should be followed for an average duration of The authors declare no conflicts of interest.
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
ACKNOWLEDGEMENT
(ANSM, 2023; CRAT, 2024; Lemberg, et al., 2018; Vidal,
2024). The treatment dosage and duration can be adjusted This manuscript is dedicated in memory of our colleague
by the physician according to the individual patient, their and friend Dr. Michael J. Gonzalez. He left a lasting impact
ability to obtain the various molecules, and the treatment on orthomolecular medicine, and we will strive to honor
results. Adaptation of the protocol to include additional him through the publication of what will be one of his final
molecules to restore health, could be considered by the contributions.
physician. These may include: vitamin K2 (Xv, et al., 2018),
vitamin E (Abraham, et al., 2019), coenzyme Q10 (Liaghat,
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16 | Journal of Orthomolecular Medicine, Volume 39, Number 3, 2024