Metformin: The Most Important Repurposed Drug in Cancer Care

How a humble diabetes drug targets the metabolic engine of cancer.

Metformin exerts multiple anticancer effects, mainly by reprogramming tumor and host metabolism and converging on mTOR and related growth/survival pathways. Numerous trials have shown that metformin, routinely used to treat diabetes, inhibits the development of cancer cells, and reduces cancer cell proliferation.

Anticancer pathways and mechanisms

Metformin has been shown to have anticancer activity both in vivo and in vitro. (1) It has been proposed that the anticancer properties of metformin result from both direct effects on cancer cells, particularly through inhibition of the AMPK/mTOR pathway, (2) and indirect effects on the host, by its blood glucose-lowering properties and anti-inflammatory effects (see Figure 1). Metformin inhibits complex I of the electron transport chain in mitochondria, putting cancer cells under bioenergetic stress and forcing them to rely on glycolysis for ATP synthesis. (3) Metformin’s inhibition of GPD2 activity alters the cytosolic redox balance, which prevents redox-dependent substrates from entering the gluconeogenic pathway. (4) Metformin suppresses protein synthesis and cell development by activating ATM (ataxia telangiectasia mutated), LKB1 (liver kinase B1), and adenosine monophosphate-activated kinase (AMPK). This reduces mTOR action. (5) By turning on AMPK, metformin can activate p53, which ultimately stops the cell cycle. (5) Peroxisome proliferator-activated receptor-gamma coactivator 1-alpha (PGC-1), a distinct molecular pathway, is upregulated due to AMPK activation following metformin exposure. Low levels of PGC-1 have been linked to poorer outcomes, and it is a transcriptional coactivator involved in mitochondrial biogenesis. Metformin boosts PGC-1 and suppresses gluconeogenesis activation. (4) Metformin interacts with the S1RT1 pathway: The sirtuin 1 (SIRT1) route, which is activated by the NAD (+)-dependent protein sirtuin 1 (SIRT1) with deacetylase activity, is another significant mechanism that connects metabolism with cell proliferation. (4) Induces G1 or G2/M arrest by regulating cyclin D1, CDKs, and p53/p21 pathways, with context‑specific engagement of tumor suppressors such as TP53, BRCA1, ATM, and CHK2.(6) Unlike most standard chemotherapy, metformin suppresses cancer stem cells, the root of cancer. (7)

Metformin regulates the EGFR and IGFR pathways, which are involved in cell growth, proliferation, and the coordination of several metabolic processes. A similar circuit performs profound functions in apoptosis and cell proliferation and is a critical axis for metabolism and cell growth. Metformin indirectly lowers systemic insulin/IGF‑1 and glucose, reducing mitogenic and metabolic support for insulin‑responsive tumors, particularly in patients with insulin resistance or diabetes. Additional research has revealed that a poor prognosis, metastasis, and disease progression are linked to elevated IGF-1 and IGF-2 expression and IGFBP-3 abnormalities. Evidence suggests that metformin treatment may prevent some of these alterations and exert an antitumor effect. Both the EGFR and IGFR pathways can boost metabolic cell modifications in a coordinated manner, acting as neoplasm promoters and forming a feedback system. (4)

Figure 1. Anticancer pathways of Metformin

Clinical studies

Meta-analyses have examined the role of metformin in the primary prevention of cancer, where it was found to significantly reduce overall cancer incidence. (8, 9) Lega et al performed a meta-analysis of 21 observational studies, evaluating the outcomes of diabetic patients with cancer who were receiving metformin. (10) In this study, metformin was associated with a reduction in all-cause mortality [HR, 0.73; 95% confidence intervals (CI), 0.64-0.83] and cancer-specific mortality (HR, 0.74; 95% CI, 0.62-0.88); patients with colorectal cancer demonstrated the greatest benefit. In a similar analysis performed by Yin et al, metformin improved overall survival in patients with lung, breast, and prostate cancer. (11) In diabetic patients with colorectal cancer Mei et al demonstrated that metformin reduced the risk of all causes of death by 44% and the specific risk of colorectal cancer death by 34%. (12) Coyle et al performed a meta-analysis of 27 observational studies which investigated the use of metformin as an adjunctive treatment for cancer.(13) The findings of this study suggested that metformin was associated with significant benefit in the early treatment of patients with colorectal and prostate cancer, particularly in those receiving radical radiotherapy. An updated meta‑analysis of 80 mostly observational studies across multiple cancers reported that metformin use was associated with better overall survival (HR 0.81), cancer‑specific survival (HR 0.79), and progression‑free survival (HR 0.76).(14) In early‑stage colorectal cancer, a meta‑analysis of largely retrospective cohorts found metformin associated with longer recurrence‑free survival (HR 0.63), overall survival (HR 0.69), and cancer‑specific survival (HR 0.58) compared with non‑metformin therapies in diabetics.(15) For renal cell carcinoma, a meta‑analysis of 10,404 patients found metformin improved cancer‑specific and progression‑free survival but did not significantly change overall survival. (16)

Types of cancers that metformin may be beneficial for

Various malignancies can be prevented with the use of metformin. In general, metformin can: i) lower cancer incidence, ii) lower cancer mortality, iii) improve cancer cell response to radiotherapy and chemotherapy, iv) optimize tumor migration and lower malignancy, v) lower relapse risk, and vi) lessen the harmful effects of androgen derivatives. (4, 5) Collective findings show that metformin has a broad spectrum of anticancer activity against breast, pancreatic, gastric, colorectal, endometrial, pancreatic prostate, non-small cell lung cancer (NSCLC), and bladder cancers. (4, 12, 13, 17-21) However, the greatest benefit may be in patients with colorectal and prostate cancer, (12, 21), particularly when used as an adjunctive therapy.

Dosing and cautions

A dose of metformin of 1,000 mg twice daily is suggested. Metformin is a remarkably safe drug with very few side effects. The most common adverse effects include abdominal or stomach discomfort, cough, hoarseness, decreased appetite, and diarrhea. Prolonged use is associated with vitamin B12 deficiency; supplementation with a B complex vitamin is therefore suggested; however, excessively high levels of B12 should be avoided as this may promote cancer proliferation. Metformin may cause very low blood glucose when combined with berberine; hence the blood glucose should be very closely monitored in patients taking this combination; if low glucose does occur, we would suggest alternating metformin and berberine (monthly). However metformin and berberine act synergystically, and should the blood sugar drop too low it may be best to reduce the dose of metformin (see post on cancer resistance)

Figure 2. Metformin: Clinical Summary

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Medical Disclaimer: The discussion of repurposed medications and nutraceuticals in this article is intended to review the scientific literature and does not constitute a recommendation for self-treatment. Decisions regarding the use of off-label therapies should be made in consultation with a qualified healthcare professional familiar with the patient’s medical history and current treatment plan. Please see the full Medical Disclaimer on the introductory page to Marik’s Cancer & Metabolic Healing Playbook.

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