Abstract
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).
Highlights
Recent understanding of the heterogeneous makeup of the cancer cells in a tumor has revealed the presence of CSCs/CSLCs [1,2], which exhibit self-renewing characteristics, ability to initiate tumor from a small number of cells that are highly chemo-resistant [3,4,5,6,7]
To examine whether metformin acts synergistically with fluorouracil and oxaliplatin (FuOx) to inhibit the growth of chemo-resistant cells, the cells were treated with incremental doses of metformin and FuOx, each alone or in combination
The results show that the combination of metformin and FuOx acts synergistically to inhibit the growth of both chemo resistant (CR) HCT-116 and CR HT-29 cells
Summary
Recent understanding of the heterogeneous makeup of the cancer cells in a tumor has revealed the presence of CSCs/CSLCs [1,2], which exhibit self-renewing characteristics, ability to initiate tumor from a small number of cells that are highly chemo-resistant [3,4,5,6,7]. Carcinoma recurrence is in part due to fact that conventional chemotherapy only targets the rapidly dividing cells that form bulk of the tumor, but spares the CSCs/CSLCs [8]. Presence of chemotherapy resistant CSCs/CSLCs in the primary tumor may in part be responsible for a failure of complete eradication of tumor resulting in its recurrence at the primary and secondary sites. Some reports indicate that metformin improved the response of human breast tumor xenografts to conventional chemotherapy by eradicating CSCs in the tumor [19,20]
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