Metformin: a potential therapeutic agent for recurrent colon cancer.
Accumulating evidence suggests that metformin, a biguanide class of anti-diabetic drugs, possesses anti-cancer properties. However, most of the studies to evaluate therapeutic efficacy of metformin have been on primary cancer. No information is available whether metformin could be effectively used for recurrent cancer, specifically colorectal cancer (CRC) that affects up to 50% of patients treated by conventional chemotherapies. Although the reasons for recurrence are not fully understood, it is thought to be due to re-emergence of chemotherapy-resistant cancer stem/stem-like cells (CSCs/CSLCs). Therefore, development of non-toxic treatment strategies targeting CSCs would be of significant therapeutic benefit. In the current investigation, we have examined the effectiveness of metformin, in combination with 5-fluorouracil and oxaliplatin (FuOx), the mainstay of colon cancer therapeutics, on survival of chemo-resistant colon cancer cells that are highly enriched in CSCs/CSLCs. Our data show that metformin acts synergistically with FuOx to (a) induce cell death in chemo resistant (CR) HT-29 and HCT-116 colon cancer cells, (b) inhibit colonospheres formation and (c) enhance colonospheres disintegration. In vitro cell culture studies have further demonstrated that the combinatorial treatment inhibits migration of CR colon cancer cells. These changes were associated with increased miRNA 145 and reduction in miRNA 21. Wnt/β-catenin signaling pathway was also down-regulated indicating its pivotal role in regulating the growth of CR colon cancer cells. Data from SCID mice xenograft model of CR HCT-116 and CR HT-29 cells show that the combination of metformin and FuOX is highly effective in inhibiting the growth of colon tumors as evidenced by ∼ 50% inhibition in growth following 5 weeks of combination treatment, when compared with the vehicle treated controls. Our current data suggest that metformin together with conventional chemotherapy could be an effective treatment regimen for recurring colorectal cancer (CRC).
Veterans Affairs Medical Center, Wayne State University, Detroit, Michigan, United States of America ; Karmanos Cancer Institute, Wayne State University, Detroit, Michigan, United States of America ; Department of Internal Medicine, Wayne State University, Detroit, Michigan, United States of America.
Pratima
P
Nangia-Makker
Veterans Affairs Medical Center, Wayne State University, Detroit, Michigan, United States of America ; Department of Internal Medicine, Wayne State University, Detroit, Michigan, United States of America.
Yingjie
Y
Yu
Veterans Affairs Medical Center, Wayne State University, Detroit, Michigan, United States of America ; Department of Internal Medicine, Wayne State University, Detroit, Michigan, United States of America.
Anita
A
Vasudevan
Veterans Affairs Medical Center, Wayne State University, Detroit, Michigan, United States of America ; Department of Internal Medicine, Wayne State University, Detroit, Michigan, United States of America.
Lulu
L
Farhana
Veterans Affairs Medical Center, Wayne State University, Detroit, Michigan, United States of America.
Sindhu G
SG
Rajendra
Veterans Affairs Medical Center, Wayne State University, Detroit, Michigan, United States of America.
Edi
E
Levi
Veterans Affairs Medical Center, Wayne State University, Detroit, Michigan, United States of America ; Karmanos Cancer Institute, Wayne State University, Detroit, Michigan, United States of America ; Department of Internal Medicine, Wayne State University, Detroit, Michigan, United States of America.
Adhip P N
AP
Majumdar
D000818:Animals; D002465:Cell Movement / Q000187:drug effects; D003110:Colonic Neoplasms / Q000188:drug therapy*; D005260:Female; D005472:Fluorouracil / Q000627:therapeutic use; D045325:HCT116 Cells; D019073:HT29 Cells; D006801:Humans; D008687:Metformin / Q000627:therapeutic use*; D051379:Mice; D016513:Mice, SCID; D009364:Neoplasm Recurrence, Local / Q000188:drug therapy; D009944:Organoplatinum Compounds / Q000627:therapeutic use; D000077150:Oxaliplatin
D009944:Organoplatinum Compounds; D000077150:Oxaliplatin; D008687:Metformin; D005472:Fluorouracil