Safe Combination of Cisplatinand Metformin Reverts theMalignant Ascites in a MouseModel to a Solid Tumor byDownregulation of ÎNp63 andInduces Tumor Dormancy via mTOR/ p21 Mechanism

Abstract

Currently, combination therapy has become the cornerstone of cancer treatment. The combination of different anti-cancer mechanisms can induce tumor cell quiescence. However, toxicity to normal tissue is the major limitation of existing combined drugs. In this study, Ehrlich ascites carcinoma (EAC) inoculated into mice was targeted with just one dose of cisplatin and later doses of metformin, a safe anti-diabetic drug with an anti-cancer effect, to maintain EAC cells in the quiescent state and secure a longer survival time without tumor recurrence. The group that underwent dual therapy had developed a delayed solid tumor instead of a malignant ascites. Induction of chemo-quiescence in the EAC cells was proven by downregulation of mechanistic target of rapamycin (mTOR) and upregulation of cyclin- dependent kinase inhibitor 1 (p21) expressions. Intriguingly, the conversion of free neoplastic cells into a solid tumor was associated with a significant decrease in ΔNp63 immunostaining in EAC cells. Taken together, a single dose of cisplatin followed by metformin doses could overcome the aggressiveness of malignant ascites by the conversion into a solid tumor, induction of chemo-quiescence and extension of survival time