Metformin and blood cancers

Abstract

Type 2 diabetes mellitus and cancer are correlated with changes in insulin signaling, a pathway that is frequently upregulated in neoplastic tissue but impaired in tissues that are classically targeted by insulin in type 2 diabetes mellitus. Many antidiabetes treatments, particularly metformin, enhance insulin signaling, but this pathway can be inhibited by specific cancer treatments. The modulation of cancer growth by metformin and of insulin sensitivity by anticancer drugs is so common that this phenomenon is being studied in hundreds of clinical trials on cancer.Many meta-analyses have consistently shown a moderate but direct effect of body mass index on the incidence of multiple myeloma and lymphoma and the elevated risk of leukemia in adults. Moreover, new epidemiological and preclinical studies indicate metformin as a therapeutic agent in patients with leukemia, lymphomas, and multiple myeloma. In this article, we review current findings on the anticancer activities of metformin and the underlying mechanisms from preclinical and ongoing studies in hematologic malignancies.

Metformin Use and Leukemia Risk in Patients With Type 2 Diabetes Mellitus

“…This is the first human study investigating the risk of leukemia after metformin use in T2DM patients. Unlike many previous studies that showed beneficial effects of metformin on the prevention of solid cancers (14) and some recent in vitro studies suggesting an inhibitory effect of metformin on the growth of leukemic cells (11,12), the findings of the present study did not support a beneficial effect of metformin on leukemia in human beings (Tables 2 and 3). In the main analyses, the risk of leukemia was neutral while comparing metformin (+) versus metformin (-) in either the intention-totreat or the per-protocol analysis ( Table 2).…”

“…Therefore, we cannot readily interpret the findings of metformin benefits on leukemic cells derived from in vitro studies (6,7,11,12). Secondly, an overall neutral effect of metformin on leukemia risk ( Table 2) and the potentially higher risk observed in patients in persistent use (per-protocol analyses, Models VI and VII, Table 3), calls for a cautious attention to the ongoing preclinical trials investigating the use of metformin as a therapeutic agent for leukemia (14). Thirdly, the possibility of differential responses to AMPK activators (such as metformin) between solid tumors and leukemia opens a new interesting venue for future research.…”

“…Some investigators envisage metformin as a new adjuvant therapeutic agent for the treatment of leukemia (8,13). However, there is lack of evidence from human studies and several clinical trials are ongoing in order to demonstrate the therapeutic effects of metformin on leukemia in patients with or without diabetes (14). On the other hand, there is paucity of data on whether metformin is preventive for the occurrence of new-onset leukemia or not.…”

Mitochondrial Bioenergetics at the Onset of Drug Resistance in Hematological Malignancies: An Overview

“…Taken together these data reflect the high involvement of mitochondria in the resistance to the drugs commonly used for the treatment of cHL, making them a highly favorable target for therapeutic manipulation via biguanides and metformin ( 99 ).…”

The association between type 1 and 2 diabetes mellitus and the risk of leukemia: a systematic review and meta-analysis of 18 cohort studies

“…Therefore, the role of these confounders in the association between T2DM and leukemia risk remains imprecise. Second, recent research has highlighted the inverse association of some antidiabetic drugs, such as metformin, with the risk of certain cancers [46][47][48][49]. Unfortunately, the role of these drugs in the relationship between DM and leukemia risk has rarely been elucidated in the included studies.…”