Metformin reverses 5-FU chemoresistance by downregulating DKK1, WNT5A, and ABCB1 expressions in gastric cancer: An experimental and bioinformatic study.

Abstract

Gastric cancer (GC) is one of the most fatal types of solid neoplasms involving individuals globally due to its chemo-resistant and metastatic nature. 5-Fluorouracil (5-FU) resistance is a complex procedure concerning the prognosis of patients with GC treated with this agent. Metformin has recently been highlighted as a member of anti-diabetic agents for its potential anti-cancer influences. In this study, we investigated the chemo-sensitivity and cell death mechanisms by which metformin moderates its effects by targeting ABCB1 (MDR1), DKK1, WNT5A, and chemo-resistance proteins (P-gp and CD44) on 5-FU-resistant gastric cancer cells. MTT assay exhibited that the combined metformin treatment with 5-FU had a more cytotoxic effect than 5-FU alone. DAPI staining proved that metformin, 5-FU, and co-treatment of them exerted an apoptotic effect on GC cells. Immunocytochemistry illustrated that metformin and its combination with 5-fluorouracil reduced the protein expressions of CD44 and P-gp, compared to the control group. The outcomes of this research displayed that the co-treatment of metformin with 5-FU significantly diminished the expressions of ABCB1, WNT5A, and DKK1 in comparison to the control. The co-treatment of these agents also decreased the expression of WNT5A and ABCB1 compared to 5-FU alone group. Overall, this study's findings demonstrated that co-treating metformin with 5-FU could overcome chemoresistance in GC cells by reducing the expression of WNT5A, MDR1, P-gp, and CD44 levels.