Metformin in the treatment of Cancer
Cancer cells use more energy(glucose) than normal cells, partly because they divide rapidly, which requires energy, and partly because they use other metabolic pathways to produce energy than normal cells. There fore they also require more insulin, a hormone needed for the incorporation of sugar into cells.
Too much insulin secretion, or hyperinsulinemia adversely affects prognosis in cancer patients and is an independent risk factor for several types of cancer, thus explaining the obesity-cancer association. Insulin can promote cancer through a direct effect on the body organs acting on the insulin/insulin-like growth factor family of receptors, or indirectly by affecting the levels of other modulators, such as insulin-like growth factors, sex hormones, and adipokines (cytokines secreted by adipose tissue). Recent evidence indicates that the abnormally high proliferative activity of premalignant and malignant cells requires high levels of nutrients to meet the increased demands for energy consumption and protein biosynthesis. Aberrations of genes involved in the intracellular metabolic pathways, such as the AMPK/LKB1 pathway, thus represent an emerging hallmark of carcinogenesis that is increasingly being recognized as a plausible preventive and therapeutic target for cancer treatment. The AMPK pathway is a central cellular key energy sensor allowing cell division, which is a highly energy-consuming process, only if cells have sufficient metabolic resources. The AMPK pathway is also activated by weight loss and physical activity.
Metformin is the drug of choice for the management of type 2 diabetes mellitus. It improves insulin resistance and glycemic control and can safely be combined with other classes of antidiabetic agents. Its primary action is to inhibit hepatic glucose production through an LKB1/AMPK–mediated mechanism; however, it also improves insulin sensitivity in peripheral tissues. Metformin lowers cardiovascular mortality by 25% compared with other oral diabetic treatments or placebo and was able to reduce the incidence of diabetes in persons at high risk, with beneficial effects persisting for at least 10 years. It has good safety profile and is well tolerated in subjects with normal glycemic levels, with transient nausea and diarrhea being the most evident side effects. Importantly, its cost is extremely low (in the order of a few cents per tablet), thus being easily accessible in clinical practice.
Interest in metformin in cancer prevention and treatment reflects the recent convergence of several areas of research. Exciting preclinical studies have shown that metformin can inhibit the growth of cancer cells both cell culture tests and animal tests. The recent evidence that metformin results in (a) initiation of an LKB1-mediated AMPK-dependent energy stress response that can adversely affect survival of cancer cell lines and (b) inhibition of cancer related genes and proteins like phosphoinositide 3-kinase/Akt/mTOR has provided a molecular basis for a direct, insulin-independent antitumor effect and strengthened the rationale to evaluate metformin in cancer clinical trials
In a meta-analysis of epidemiologic studies(1) to assess the effect of metformin on cancer incidence and mortality in diabetic patients, eleven studies were selected for relevance in terms of intervention, population studied, independence, and reporting of cancer incidence or mortality data, reporting 4,042 cancer events and 529 cancer deaths. A 31% reduction in overall summary relative risk (0.69; 95% confidence interval, 0.61-0.79) was found in subjects taking metformin compared with other antidiabetic drugs. The inverse association was significant for pancreatic and hepatocellular cancer, and less significant for colon, breast, and prostate cancer. A trend to a dose-response relationship was noted. Metformin was associated with a decreased risk of cancer incidence compared with other treatments among diabetic patients.
The observation that metformin was associated with greater risk reduction in specific major cancer killers such as colon, pancreatic, and breast cancer is consistent with the notion that diabetes or elevated insulin and glucose levels play an important role in the development of these tumors and has important clinical research implications. For instance, metformin has been shown to reverse the effects of the high-energy diet on the growth of colon cancer cells and, in a recent pilot clinical trial on 26 nondiabetic patients with a possible precancerous lesion called aberrant crypt foci, metformin at a dose 250 mg/d for 1 month suppressed the mean number of aberrant crypt foci per patient, compared with control/untreated subjects. Moreover, metformin can prevent the promotional effect of high-fat diet on pancreatic carcinogenesis in the hamster and inhibits pancreatic cancer growth in mice.. As for breast cancer, metformin at low doses was shown to inhibit cellular transformation and selectively killed cancer stem cells in four genetically different types of breast cancer(6). Several preclinical trials are currently under way to assess the antiproliferative effect of metformin on malignant, premalignant, and hyperplastic breast cells.
The association of metformin with reduced cancer mortality provides the rationale for the study of metformin in the cancer treatment setting. A recent retrospective study in breast cancer patients showed that diabetic cancer patients treated with metformin and neoadjuvant chemotherapy had a higher pathologic complete response rate than the control groups. A phase III adjuvant trial of metformin is currently being launched by National Cancer Institute Canada and National Cancer Institute United States to assess the efficacy of metformin in reducing breast cancer recurrence in 3,582 women with stage I and II breast cancer (2).
At the European Institute of Oncology, the Division of Cancer Prevention and Genetics is planning to conduct a clinical trial to evaluate the activity of metformin on tumor cell proliferation in breast cancer patients undergoing surgery. It will be a presurgical randomized, double blind, placebo-controlled phase II biomarker trial: 100 histologically confirmed breast cancer patients will be randomly assigned to metformin (850 mg twice/daily) or placebo for 28+7 days till surgery to assess drug activity on tumor proliferation, as measured by Ki-67. The confirmation of the efficacy of metformin on cancer cell proliferation may lead the way to larger chemoprevention clinical trials(4).
Therefore we have recently started to give many of our cancer patients at Humlegården metformin.