Abstract
Metformin is the most used drug for type 2 diabetes (T2DM). Its antitumor activity has been described by clinical studies showing reduced risk of cancer development in T2DM patients, as well as management of T2DM compared with those receiving other glucose-lowering drugs. Metformin has a plethora of molecular actions in cancer cells. This review focused on in vitro data on the action mechanisms of metformin on thyroid, prostate and head and neck cancer. AMPK activation regulating specific downstream targets is a constant antineoplastic activity in different types of cancer; however, AMPK-independent mechanisms are also relevant. In vitro evidence makes it clear that depending on the type of tumor, metformin has different actions; its effects may be modulated by different cell conditions (for instance, presence of HPV infection), or it may regulate tissue-specific factors, such as the Na+/I− symporter (NIS) and androgen receptors. The hallmarks of cancer are a set of functional features acquired by the cell during malignant development. In vitro studies show that metformin regulates almost all the hallmarks of cancer. Interestingly, metformin is one of these therapeutic agents with the potential to synergize with other chemotherapeutic agents, with low cost, low side effects and high positive consequences. Some questions are still challenging: Are metformin in vitro data able to translate from bench to bedside? Does metformin affect drug resistance? Can metformin be used as a generic anticancer drug for all types of tumors? Which are the specific actions of metformin on the peculiarities of each type of cancer? Several clinical trials are in progress or have been concluded for repurposing metformin as an anticancer drug. The continuous efforts in the field and future in vitro studies will be essential to corroborate clinical trials results and to elucidate the raised questions.
Highlights
Since the first reported use of metformin for diabetes treatment in 1957, millions of people have been taking this synthetic biguanide for type 2 diabetes management worldwide [1]
adenosine monophosphateprotein kinase (AMPK) is activated through the tumor suppressor liver resulting in inhibition of the mammalian target of rapamycin pathway, activated kinase B1, resulting in inhibition of the mammalian target of rapamycin pathway, in many human cancers [6]
Thyroid cancer (TC) derived from follicular cells includes differentiated thyroid cancer (DTC) with papillary (PTC) or follicular (FTC) histology (80% of cases) and undifferentiated and poorly differentiated TC (1–2% of cases)
Summary
Since the first reported use of metformin for diabetes treatment in 1957, millions of people have been taking this synthetic biguanide for type 2 diabetes management worldwide [1]. Attention has been brought to this safe and inexpensive drug for its antitumor activity from a clinical report in 2005 that associated the use of metformin with the decreased risk of cancer in patients with type 2 diabetes [2]. AMPK is activated through the tumor suppressor liver resulting in inhibition of the mammalian target of rapamycin pathway (mTOR), activated kinase B1, resulting in inhibition of the mammalian target of rapamycin pathway (mTOR), in many human cancers [6]. Figure summarizes the molecular pathways modulated by metformin and head and neck cancers. X-C Motif Chemokine Ligand 12 (CXCL12), Cyclooxygenase 2 (COX2), DNA-dependent protein kinase C-X-C (DNA-PK), reticulum (CXCR4),. Kinase B1 (S6K1), Ribosomal protein S6 (S6), Small heterodimer partner–interacting leucine zipper (SMILE), Signal Transducer And Activator Of Transcription (STAT3), Transforming Growth Factor.
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