Molecular and Cellular Mechanisms of Metformin in Cervical Cancer

Abstract

Cervical cancer is one of the major gynecologic malignancies worldwide. Treatment options include chemotherapy, surgical resection, radiotherapy, or a combination of these treatments; however, relapse and recurrence may occur, and the outcome may not be favorable. Metformin is an established, safe, well-tolerated drug used in the treatment of type 2 diabetes; it can be safely combined with other antidiabetic agents. Diabetes, possibly associated with an increased site-specific cancer risk, may relate to the progression or initiation of specific types of cancer. The potential effects of metformin in terms of cancer prevention and therapy have been widely studied, and a number of studies have indicated its potential role in cancer treatment. The most frequently proposed mechanism underlying the diabetes–cancer association is insulin resistance, which leads to secondary hyperinsulinemia; furthermore, insulin may exert mitogenic effects through the insulin-like growth factor 1 (IGF-1) receptor, and hyperglycemia may worsen carcinogenesis through the induction of oxidative stress. Evidence has suggested clinical benefits of metformin in the treatment of gynecologic cancers. Combining current anticancer drugs with metformin may increase their efficacy and diminish adverse drug reactions. Accumulating evidence is indicating that metformin exerts anticancer effects alone or in combination with other agents in cervical cancer in vitro and in vivo. Metformin might thus serve as an adjunct therapeutic agent for cervical cancer. Here, we reviewed the potential anticancer effects of metformin against cervical cancer and discussed possible underlying mechanisms.

Diabetes associated with cervical carcinoma among high-risk HPV-infected patients with cytologically diagnosed high grade squamous intraepithelial lesion

“…In addition, poor glycemic control can lead to the production of advanced glycation end products, leading to oxidative stress and DNA damage ( 26 ). Poor glycemic control can lead to hyperinsulinemia, and insulin may exert mitogenic effects through the insulin-like growth factor 1 (IGF-1) receptor, thereby stimulating cell proliferation and inhibiting apoptosis ( 7 , 8 , 26 ). DM patients with poor glycemic control are often characterized by an enhanced chronic inflammatory state with increased levels of inflammatory cytokines TNF-α and IL-6.…”

“…Human papillomaviruses (HPV16 and HPV18) are strongly associated with the development of cervical cancer in women ( 5 ). Diabetes causes metabolic disorders and immune changes that may be potential triggers of cervical cancer ( 6 , 7 ). Therefore, diabetes is not a “bystander” to cervical cancer.…”

Combinatorial therapy of Cynodon dactylon and Metformin with Cisplatin in cervical cancer

“…However, the combination of metformin along with cisplatin (high dose of metformin, and lower dose of cisplatin) is more effective for apoptosis and cancer growth suppression in cervical cancer cell lines. This combination reduces the dosedependent toxicity and controls the energy metabolism by induction of AMP-activated AMPK and inhibition of mTOR [51]. Similarly, the combinatorial effect of metformin and caffeic acid along with cisplatin resulted in a reprogrammed cell cycle, apoptosis and resensitization of SiHa cervical cancer cells [52].…”

Metformin in selected malignancies in women

“…The mechanism of metformin action in cervical cancer is complex. It reduces the concentration of circulating insulin, which has a strong mitogenic effect through the insulinlike growth factor 1 receptor (IGF-1), and by reducing hyperglycemia, it reduces oxidative stress that intensifies carcinogenesis [47].…”