Synergistic effect of metformin and medroxyprogesterone 17‑acetate on the development of endometrial cancer

Abstract

Accumulating data indicate that insulin resistance and unopposed estrogen are important risk factors of endometrial cancer (EC). Medroxyprogesterone 17‑acetate (MPA) has been used in the treatment of EC for many years. However, the therapeutic effect of this agent on EC has not been satisfactory. 36 arMetformin was recently reported to be a promising agent for the treatment of malignant diseases including EC. However, information on the synergistic effect of the two agents in EC is limited. With the aim to evaluate the synergistic effect of metformin and MPA, we conducted the present study in vitro and in vivo. We found that the combined application of metformin and MPA significantly inhibited the proliferation of the Ishikawa cells and arrested the cells in the G0/G1 phase. Furthermore, the apoptosis rate of the Ishikawa cells was significantly increased. In the animal study, the development of the xenograft tumors was significantly suppressed by the combined application of the two agents. Further investigation revealed that the synergistic inhibitory effect of the two agents on EC can be at least partly, explained by the decreased expression of cyclin D1 and cyclin E. The results of the current study provide novel insights into the treatment of EC.

Metformin Promotes Anti-tumor Biomarkers in Human Endometrial Cancer Cells

“…Taken together, our results suggest that MET may elicit early (ERα, KLF9, KLF4, and DKK1) and late (PGR, PGR-B, and PTEN) responses on PGR/ERα gene networks and that maintenance of some of these MET effects on gene expression (ERα, KLF4, DKK1, and PGR) may require additional/continuous exposure to MET, possibly involving the activation of other signaling pathways. In this regard, the recent report that the development of EC tumors in a xenograft mouse model was significantly suppressed by the combined administration of MET and medroxyprogesterone acetate, when compared to individual treatments [47], is consistent with this possibility. Moreover, induction of PGR expression in Ishikawa cells by MET, which was shown to be mediated by the activation of the AMPK pathway at pharmacological (mM) doses, was only partially inhibited by an AMPK inhibitor [48].…”

Outcomes of women treated with progestin and metformin for atypical endometrial hyperplasia and early endometrial cancer: a systematic review and meta-analysis

“…Metformin has also been shown to have a synergistic impact on progesterone's inhibitory effect on endometrial cell proliferation. [9][10][11] Growing evidence in the literature suggests that metformin may be a beneficial adjunctive therapy, with a synergistic effect alongside progestin, in the suppression of endometrial proliferation.…”

Metformin Enhances Nomegestrol Acetate Suppressing Growth of Endometrial Cancer Cells and May Correlate to Downregulating mTOR Activity In Vitro and In Vivo

“…Clinically, metformin inhibited EC relapse after MPA therapy [24] and may prolong the overall survival of patients with EC [25,26], but the effects of adjunct metformin were not confirmed in prospective controlled trials [26]. Currently, there is only one experimental paper that describes that metformin (250 mg/kg) strengthened the inhibitory effect of MPA on xenograft tumors of nude mice loaded with Ishikawa EC cells [27]. Accordingly, the efficacy of combining metformin and progestins in EC treatment still needs to be studied.…”