Abstract
Metformin is most widely prescribed for type 2 diabetes. Recently, evidences have shown that metformin has anticancer effects on pancreatic-, colorectal-, ovarian-, and other cancers. Because metformin has less adverse effects and is inexpensive, it could be a useful chemo-therapeutic agent with anticancer effects. In this study, we demonstrated metformin inhibited by cell proliferation, cell migration ability, clonogenic ability, and cancer stem cell population. Metformin also induced cell cycle arrest in parental-(SNU-C5), and 5-Fu resistant-colorectal cancer cell line (SNU-C5_5FuR). Moreover, a treatment that combines 5-Fu and metformin was found to have a synergistic effect on the cell proliferation rate, especially in SNU-C5_5FuR, which was mediated by the activation of AMPK pathway and NF-ƙB pathway, well-known metformin mechanisms. In this study, we suggested novel anticancer mechanism of metformin that inhibited DNA replication machinery, such as the MCM family in SNU-C5_5FuR. In conclusion, we provided that how metformin acts as not only a chemo-sensitizer, but also as a synergistic effector of 5-Fu in the 5-Fu resistant-cell line. We speculate that metformin used for adjuvant therapy is effective on 5-Fu resistant cancer cells.
Highlights
Colorectal cancer is the third most diagnosed cancer with an annual estimated death of 60,000 [1]. 5-Fluorouracil (5-Fu) is the standard chemotherapeutic agent in colorectal cancer that acts as an antimetabolite drug through thymidylate synthase (TS) inhibition and incorporated into nucleic acid, DNA, and RNA
We showed metformin selectively affecting cell proliferation and metastatic behavior on 5-Fu resistant-colorectal cancer cell lines caused by the inhibition of DNA replication machinery
We investigated if metformin affects cell proliferation and the cell cycle in parental-(SNU-C5) or 5-Fu resistant colorectal cancer cell lines (SNU-C5_5FuR)
Summary
Colorectal cancer is the third most diagnosed cancer with an annual estimated death of 60,000 [1]. 5-Fluorouracil (5-Fu) is the standard chemotherapeutic agent in colorectal cancer that acts as an antimetabolite drug through thymidylate synthase (TS) inhibition and incorporated into nucleic acid, DNA, and RNA. There are some studies that state metformin is related to anticancer effects: metformin significantly decreased the incidence risk of pancreatic-, colorectal-, and ovarian cancers [7,8,9,10], as well as various cancer cell lines [11,12,13,14,15]. Metformin influences apoptosis and cell cycle arrest, which reduces cancer cell populations [16, 17]. Metformin activates AMPK after LKB1 and sequentially inactivates mTOR. Along this pathway, p53 is activated according to autophagy and decreased protein synthesis. The cell cycle is arrested as a result, which means that metformin mechanism is related www.impactjournals.com/oncotarget to the chemotherapeutic effect. In SW620 colon cancer cell line, metformin affects cell proliferation, apoptosis, and cell cycle via selectively targeted CD133+ cancer stem cell populations [19]
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