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).