Antiproliferative and metabolic effects of metformin in a preoperative window clinical trial for endometrial cancer

Abstract

We conducted a preoperative window study of metformin in endometrial cancer (EC) patients and evaluated its antiproliferative, molecular and metabolic effects. Twenty obese women with endometrioid EC were treated with metformin (850 mg) daily for up to 4 weeks prior to surgical staging. Expression of the proliferation marker Ki-67, estrogen receptor (ER), progesterone receptor (PR), adenosine monophosphate-activated protein kinase (AMPK), and downstream targets of the mammalian target of rapamycin (mTOR) pathway were measured by immunohistochemistry. Global, untargeted metabolomics analysis of serum pre- and postmetformin treatment, and matched tumor, was performed. Metformin reduced proliferation by 11.75% (P = 0.008) based on the comparison of pre- and posttreatment endometrial tumors. A total of 65% of patients responded to metformin as defined by a decrease in Ki-67 staining in their endometrial tumors post-treatment. Metformin decreased expression of phosphorylated (p)-AMPK (P = 0.00001), p-Akt (P = 0.0002), p-S6 (51.2%, P = 0.0002), p-4E-BP-1 (P = 0.001), and ER (P = 0.0002) but not PR expression. Metabolomic profiling of serum indicated that responders versus nonresponders to treatment were more sensitive to metformin's effects on induction of lipolysis, which correlated with increased fatty acid oxidation and glycogen metabolism in matched tumors. In conclusion, metformin reduced tumor proliferation in a pre-operative window study in obese EC patients, with dramatic effects on inhibition of the mTOR pathway. Metformin induced a shift in lipid and glycogen metabolism that was more pronounced in the serum and tumors of responders versus nonresponders to treatment.This study provides support for therapeutic clinical trials of metformin in obese patients with EC.

Metformin and Breast Cancer Stage at Diagnosis: A Population-Based Study

“…In preclinical studies, metformin was found to inhibit tumour spread and to reduce tumour growth 23,24 . In short-term window-of-opportunity studies, metformin was shown to affect tumour growth both through indirect, insulin-dependent pathways 6,7,25 and by activating ampk pathways to directly affect cancer cells 26,27 . However, in larger epidemiologic studies, those actions have not translated into an improvement in tumour stage or cancer burden for either breast cancer or other cancers.…”

Dissecting the Dual Role of AMPK in Cancer: From Experimental to Human Studies

“…phase 0) trials have been conducted to evaluate metformin administration in the time window between cancer diagnosis and surgery. These studies show mixed results for tumor p-AMPKα at Thr172 expression before and after metformin use (ranging from 850–2250 mg/day): p-AMPKα protein expression was increased in one study of endometrial cancer patients (121), decreased in another study of endometrial cancer patients (122), and unchanged in two studies of endometrial (123) and prostate (124) cancer patients. Thus, a direct link between short-term metformin use and AMPK activation in targeted tissue is unclear.…”

Metformin as target metabolic drug in oncology

“…Многие терапевтические эффекты метформина объясняются его активирующим влиянием на АМФ-активируемую протеинкиназу, которая определяет энергетический статус клетки [4,31]. Действуя на АМФ-ПК, метформин в то же время является ингибитором инициации трансляции [32].…”

“…Интересно, что метформин превентирует развитие не только рака кишечника, но и уменьшает развитие до-брокачественных новообразований толстой кишки [2]. Авторы показали, что метформин уменьшает пролифера-цию опухоли в эндометрии [4]. Также описано, что при-менение метформина снижает заболеваемость раком поджелудочной железы [5].…”