Metformin as a promising therapeutic agent for papillary thyroid cancer: Mechanisms of antitumor and pro-apoptotic activity

• In PTC, apoptosis inhibition is a prominent feature that contributes to tumor development. • PTC cells may evade apoptosis by altering Bcl-2 family proteins, promoting cell survival. • Overexpression of survivin, cyclin D1, and mTOR in PTC cells promotes tumor survival. • Metformin targets apoptosis-related proteins, suggesting its use in adjuvant PTC therapy. • Metformin inhibits TC growth, promotes apoptosis, and may enhance RAI treatment efficacy. Metformin, a well-established modulator of various metabolic pathways, including those regulating glucose and lipid metabolism, hormone synthesis, oxidative stress, and apoptosis, has garnered increasing interest in the field of cancer treatment and prevention. Clinical studies have indicated a reduced incidence of cancer in patients with type 2 diabetes mellitus who were treated with metformin. Emerging research has illuminated the underlying antitumor mechanisms of metformin, primarily through its activation of AMP-activated protein kinase (AMPK) and the concomitant inhibition of the mammalian target of rapamycin (mTOR) pathway. These molecular events culminate in the induction of apoptosis. Notably, investigations involving human papillary thyroid cancer (PTC) cells have demonstrated metformin's antimitogenic activity, which is closely linked to its ability to inhibit cellular proliferation and metastasis. Given the rising incidence of PTC in recent decades, there is an urgent need to explore innovative and minimally invasive treatment strategies. Consequently, the exploration of metformin as an adjunctive therapy for PTC has become a topic of critical importance, as it has the potential to effectively impede tumor cell proliferation and promote apoptosis. However, it is important to recognize the current limitations in the evidence supporting the anticancer properties of metformin. Most findings stem from in vitro studies, which may not fully capture the complexities of human physiology. Therefore, the primary objective of this literature review is to comprehensively synthesize recent advancements regarding metformin's anticancer and proapoptotic effects, with particular emphasis on its role in ongoing clinical trials targeting PTC intervention.