Introduction: Colon cancer is the third most common cancer and one of leading cause of cancer-related death. Surgically unremovable colon cancer is treated by chemotherapeutic agents but the responses are not satisfactory. Activation of PI3K/Akt/mTOR pathway has been associated with drug resistance. Targeting therapy to inhibit the PI3K/Akt/mTOR could be an effective approach. Vertical inhibition of the pathway by dual inhibitors such as PI-103, BEZ235 and PLX4720, which targets both PI3K and mTOR, has been shown to inhibit pathway more effectively.
Objectives: In this study we tested the effect of dual inhibitors of PI3K and mTOR on colon cancer stem cells isolated from HCT116 cell line. Cancer stem cells are known to resist to chemotherapeutic agents. We also tested dual inhibitors on insulin-induced drug resistance to chemotherapeutic agents.
Methods: Colon cancer stem cells were isolated and cultured in stem cell special medium. The stem cell markers were characterised by flow-cytometry. The effect of dual inhibitors on cancer stem cells was investigated in sphere formation and cell proliferation. The change of the activity of PI3K/Akt/mTOR pathway was determined by Western blotting.
Results: Dual inhibitors decreased sphere formation of colon cancer stem cells. They also decreased stem cell proliferation in a dose-dependent fashion at concentrations. Dual inhibitors also overcome insulin-induced drug resistance on colon cancer cell lines. Western blotting showed that dual inhibitors reduced phosphorated Akt markedly, indicating its inhibitory effect on the pathway.
Conclusion: Vertical inhibition of the PI3K/Akt/mTOR by dual inhibitors are effective on colon cancer stem cells by inhibiting sphere formation and cell proliferation via inhibition of PI3K/Akt/mTOR pathway. It can also overcome insulin-induced drug resistance.
Note: JC and WG equally contribute the study.