Abstract
Metformin, which is a drug commonly used to treat type 2 diabetes, has shown anti-tumor effects in numerous experimental, epidemiologic, observational, and clinical studies. Here, we report a new metformin derivative, metformin-butyrate (MFB). Compared to metformin-HCl, it more potently activates AMPK, inhibits mTOR, and impairs cell cycle progression at S and G2/M phases. Moreover, MFB inhibits the mammosphere formation of breast cancer cells and shows cytotoxic effects against CD44+CD24−/low populations in vitro and in vivo, indicating that it might have preferential effects on the cancer stem cell population. MFB showed synergistic cytotoxicity with docetaxel and cisplatin, and MFB pretreatment of breast cancer cells prior to their injection into the mammary fat pads of mice significantly decreased the obtained xenograft tumor volumes, compared with untreated or metformin-pretreated cells. Overall, MFB showed greater anti-neoplastic activity and greater efficacies in targeting the G2/M phase and breast cancer stem cell population, compared to metformin-HCl. This suggests that MFB may be a promising therapeutic agent against aggressive and resistant breast cancers.
Highlights
Metformin (1, 1-dimethylbiguanide hydrochloride), which is the most widely used anti-diabetic drug for type 2 diabetes, has recently been shown to possess strong anti-cancer effects [1]
To identify the metformin derivatives with the highest cytotoxicity against cancer cells, we screened a series of metformin analogs for their ability to decrease viability in breast cancer cell lines
Nineteen breast cancer cell lines, including the luminal and basal A and B subtypes, were treated with 0.01 to 100 mM of each metformin analog for 48 h, and cytotoxicity was compared to that conferred by metformin
Summary
Metformin (1, 1-dimethylbiguanide hydrochloride), which is the most widely used anti-diabetic drug for type 2 diabetes, has recently been shown to possess strong anti-cancer effects [1]. Recent epidemiologic studies have indicated that the use of metformin in type II diabetic patients significantly suppresses the development of cancers and lowered cancer-related mortality [13]. A retrospective study found that the addition of metformin to neoadjuvant chemotherapy yielded a significantly higher rate of pathologic complete response (pCR) in diabetic patients with breast cancer [4]. Preclinical studies in animal model systems have shown that metformin decreases the tumor growth of breast [5, 6], colon [7], and pancreatic [8] cancers. Metformin appears to be an effective means of dealing with cancer. Metformin has been shown to affect AMPK and mTOR signaling activity [9,10,11,12,13] and modulate cell cycle-related molecules to cause G1 arrest and apoptosis [14,15,16]
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