{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,18]],"date-time":"2026-09-18T16:13:11Z","timestamp":1789747991412,"version":"4.0.1"},"reference-count":134,"publisher":"MDPI AG","issue":"3","license":[{"start":{"date-parts":[[2022,2,24]],"date-time":"2022-02-24T00:00:00Z","timestamp":1645660800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Biomolecules"],"abstract":"<jats:p>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\u2212 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.<\/jats:p>","DOI":"10.3390\/biom12030357","type":"journal-article","created":{"date-parts":[[2022,2,24]],"date-time":"2022-02-24T07:22:35Z","timestamp":1645687355000},"page":"357","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":41,"title":["Metformin and Cancer Hallmarks: Molecular Mechanisms in Thyroid, Prostate and Head and Neck Cancer Models"],"prefix":"10.3390","volume":"12","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2778-7697","authenticated-orcid":false,"given":"Mirian Galliote","family":"Morale","sequence":"first","affiliation":[{"name":"Department of Biological Sciences, Federal University of S\u00e3o Paulo, Diadema, Rua Pedro de Toledo 669, 11\u00b0 Andar, S\u00e3o Paulo 04039-032, Brazil"},{"name":"Laboratory of Cancer Molecular Biology, Federal University of S\u00e3o Paulo, Rua Pedro de Toledo 669, 11\u00b0 Andar, S\u00e3o Paulo 04039-032, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rodrigo Esaki","family":"Tamura","sequence":"additional","affiliation":[{"name":"Department of Biological Sciences, Federal University of S\u00e3o Paulo, Diadema, Rua Pedro de Toledo 669, 11\u00b0 Andar, S\u00e3o Paulo 04039-032, Brazil"},{"name":"Laboratory of Cancer Molecular Biology, Federal University of S\u00e3o Paulo, Rua Pedro de Toledo 669, 11\u00b0 Andar, S\u00e3o Paulo 04039-032, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ileana Gabriela Sanchez","family":"Rubio","sequence":"additional","affiliation":[{"name":"Department of Biological Sciences, Federal University of S\u00e3o Paulo, Diadema, Rua Pedro de Toledo 669, 11\u00b0 Andar, S\u00e3o Paulo 04039-032, Brazil"},{"name":"Laboratory of Cancer Molecular Biology, Federal University of S\u00e3o Paulo, Rua Pedro de Toledo 669, 11\u00b0 Andar, S\u00e3o Paulo 04039-032, Brazil"},{"name":"Thyroid Molecular Sciences Laboratory, Federal University of S\u00e3o Paulo, Rua Pedro de Toledo 669, 11\u00b0 Andar, S\u00e3o Paulo 04039-032, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,2,24]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1566","DOI":"10.1007\/s00125-017-4318-z","article-title":"Metformin: Historical overview","volume":"60","author":"Bailey","year":"2017","journal-title":"Diabetologia"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1304","DOI":"10.1136\/bmj.38415.708634.F7","article-title":"Metformin and Reduced Risk of Cancer in Diabetic Patients","volume":"330","author":"Evans","year":"2005","journal-title":"Br. 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