Review of the Hybrid Orthomolecular Protocol for Cancer Treatment

The article “Targeting the Mitochondrial-Stem Cell Connection in Cancer Treatment: A Hybrid Orthomolecular Protocol” introduces a novel approach to cancer therapy by targeting the metabolic dysfunction in cancer stem cells (CSCs) via mitochondrial interventions. The theory behind this approach called the Mitochondrial-Stem Cell Connection (MSCC), integrates insights from the cancer stem cell and metabolic theories of cancer. According to this concept, cancer arises when oxidative phosphorylation (OxPhos) becomes insufficient in stem cells, leading to the formation of CSCs, which drive tumor initiation and metastasis. This review looks at the anticancer mechanisms of the orthomolecular protocol and its components while highlighting some caveats associated with each substance.

The Role of Mitochondria in Cancer

Cancer cells, including CSCs, typically rely on aerobic glycolysis (Warburg effect) for energy production, favoring glucose and glutamine metabolism over OxPhos. This metabolic reprogramming enables rapid proliferation, resistance to apoptosis, and immune evasion. The MSCC protocol aims to restore OxPhos, target CSCs, and inhibit glucose and glutamine metabolism to reduce cancer growth and metastasis. The protocol involves using orthomolecules (high-dose vitamins), repurposed drugs, and lifestyle interventions to enhance mitochondrial function, promote oxidative stress in cancer cells, and disrupt their metabolic pathways.

Vitamin C

Vitamin C plays a dual role in cancer treatment, acting as an antioxidant and pro-oxidant, depending on the dosage and administration method. In the context of cancer, intravenous high-dose vitamin C has been shown to selectively induce oxidative stress in cancer cells, particularly by generating hydrogen peroxide. This oxidative stress targets cancer cells, including CSCs, by increasing reactive oxygen species (ROS) and damaging their mitochondria, which can lead to apoptosis and inhibit tumor growth.

Caveat: While high-dose vitamin C shows promise, studies also reveal variability in its efficacy. For instance, in some cancers, antioxidant supplementation, including vitamin C, might protect cancer cells from oxidative damage caused by chemotherapy and radiation. This suggests that vitamin C could have dual roles, depending on tumor type and stage, and requires precise dosing to avoid unintended protective effects for cancer cells.

Vitamin D

Vitamin D regulates mitochondrial function and energy metabolism, exhibiting antiproliferative and anti-metastatic effects. It enhances OxPhos, reversing the Warburg effect in CSCs and promoting apoptosis. Furthermore, vitamin D has shown preventive effects in various cancers, particularly in patients with low baseline levels of the vitamin.

Caveat: Despite these benefits, studies also show inconsistent results regarding vitamin D supplementation. For instance, high doses of vitamin D may lead to hypercalcemia or other metabolic disturbances in some cancers, particularly in patients with compromised kidney function. Additionally, the optimal dose of vitamin D varies widely between individuals.

Zinc

Zinc supports mitochondrial health by protecting mitochondria from oxidative damage. It also induces apoptosis in cancer cells by inhibiting key metabolic pathways such as glycolysis and glutaminolysis. Zinc supplementation can reduce the stemness of CSCs, promoting their differentiation and sensitizing them to conventional therapies.

Caveat: While zinc has shown efficacy in reducing cancer cell viability, excess zinc can have adverse effects. Studies have demonstrated that excessive zinc can induce mitochondrial dysfunction, leading to hypocupremia and toxicity in both cancerous and healthy cells. Zinc's effect on immune modulation remains complex; high doses could potentially suppress the immune response, undermining the immune system’s ability to fight cancer. Furthermore, excessive zinc accumulation in muscles has been linked to the development of cachexia in cancer patients.

Ivermectin

Ivermectin, an antiparasitic drug, exhibits anticancer properties by targeting mitochondrial function and inducing autophagy in cancer cells. It has been shown to selectively inhibit CSCs by inducing mitochondrial-mediated apoptosis. Ivermectin also suppresses glycolysis, enhancing oxidative stress in cancer cells and disrupting their metabolic flexibility.

Caveat: While ivermectin shows potential as an anticancer agent, its broad-spectrum effects on various cellular pathways raise concerns. For example, ivermectin has been associated with immune modulation [1], and there is evidence that it could alter macrophage activity within the tumor microenvironment. Studies have suggested that ivermectin may increase M2 macrophage polarization, linked to immune suppression and tumor progression [2]. 

Benzimidazoles (Mebendazole, Fenbendazole)

Benzimidazoles, particularly mebendazole and fenbendazole, have emerged as promising anticancer agents. These drugs disrupt microtubule function, inhibit glycolysis, and induce apoptosis in cancer cells by damaging mitochondrial integrity. They are particularly effective against CSCs and resistant cancer cells. Fenbendazole, for instance, has been shown to target CSCs in both in vitro and in vivo cancer models, inhibiting tumor growth.

Caveat: In a study examining fenbendazole’s effects on EL-4 cells and a mouse T lymphoma model, researchers found that fenbendazole increased the expression of immune-modulatory markers such as PD-L1 and CD86, which could influence T-cell immunity [3]. However, these findings also revealed increased M2 macrophages within the tumor microenvironment, typically associated with immunosuppression and tumor progression. Thus, fenbendazole might contribute to an immunosuppressive tumor microenvironment despite its direct anticancer effects.

Ketogenic Diet

The ketogenic diet restricts glucose availability, forcing cancer cells to rely on OxPhos for energy. This shift inhibits cancer cell proliferation and induces apoptosis in glucose-dependent cancer cells. The diet is particularly effective when combined with OxPhos-enhancing therapies, such as high-dose vitamin C and repurposed drugs like ivermectin and mebendazole.

Caveat: Prolonged adherence to a ketogenic diet can cause nutrient deficiencies, electrolyte imbalances, and impaired kidney function. Moreover, certain cancer cells, particularly those with metabolic plasticity, may adapt to utilize alternative fuel sources such as glutamine, reducing the efficacy of glucose restriction alone.

Fasting

Fasting induces autophagy, a process that eliminates damaged mitochondria and promotes the regeneration of healthy ones. By depriving cancer cells of glucose and glutamine, fasting can enhance mitochondrial function in normal cells while inducing apoptosis in cancer cells.

Caveat: Although fasting has shown anticancer effects, it can also lead to muscle loss, nutrient deficiencies, and weakened immune function in cancer patients, particularly those with advanced disease or low body mass index. Fasting should be carefully monitored in these patients, as malnutrition could exacerbate their condition and limit the effectiveness of other therapies.

Physical Activity and Hyperbaric Oxygen Therapy (HBOT)

Physical activity improves mitochondrial function and enhances OxPhos, which supports the overall goal of restoring healthy energy metabolism in cancer cells. Hyperbaric oxygen therapy (HBOT) increases oxygen availability, promoting OxPhos and reducing tumor hypoxia. When combined with a ketogenic diet, HBOT can amplify oxidative stress in cancer cells, leading to apoptosis.

Caveat: The effects of HBOT on cancer are not fully understood, and there is a risk that increased oxygen availability could stimulate angiogenesis in some tumors, potentially promoting growth rather than inhibiting it. Therefore, HBOT must be used cautiously and with other therapies that suppress angiogenesis and metastasis.

The hybrid orthomolecular protocol offers a multifaceted approach to cancer treatment by targeting the metabolic vulnerabilities of cancer cells, particularly CSCs. While the protocol holds potential, the caveats associated with each component highlight the need for individualized treatments. The combination of orthomolecules, repurposed drugs, and dietary interventions must be carefully tailored to each patient's unique metabolic profile to optimize efficacy and minimize adverse effects.

[1] Dias de Melo, Guilherme & Lazarini, Françoise & Larrous, Florence & Feige, Lena & Kornobis, Etienne & Levallois, Sylvain & Marchio, Agnes & Kergoat, Lauriane & Hardy, David & Cokelaer, Thomas & Pineau, Pascal & Lecuit, Marc & Lledo, Pierre-Marie & Changeux, Jean‐Pierre & Bourhy, Hervé. (2021). Attenuation of clinical and immunological outcomes during SARS‐CoV‐2 infection by ivermectin. EMBO Molecular Medicine. 13. 10.15252/emmm.202114122. 

[2] Boutilier, Ava. (2021). Macrophage Polarization States in the Tumor Microenvironment. International Journal of Molecular Sciences. 22. 6995. 10.3390/ijms22136995. 

[3] Jung, Haebeen & Kim, Si-Yeon & Joo, Hong-Gu. (2023). Fenbendazole Exhibits Differential Anticancer Effects In Vitro and In Vivo in Models of Mouse Lymphoma. Current Issues in Molecular Biology. 45. 8925-8938. 10.3390/cimb45110560.