Ponatinib and gossypol act in synergy to suppress colorectal cancer cells by modulating apoptosis/autophagy crosstalk and inhibiting the FGF19/FGFR4 axis

Objective: To evaluate the efficacy of ponatinib plus gossypol against colorectal cancer HCT-116 and Caco-2 cells.Methods: Cells were treated with ponatinib and/or gossypol at increasing concentrations to evaluate synergistic drug interactions by combination index. Cell viability, FGF19/FGFR4, and apoptotic and autophagic cell death were studied.Results: Ponatinib(1.25-40 μM) and gossypol(2.5-80 μM)monotherapy inhibited HCT-116 and Caco-2 cell viability in a doseand time-dependent manner. The combination of ponatinib and gossypol at a ratio of 1 to 2 significantly decreased cell viability(P<0.05), with a > 2-and > 4-fold reduction in IC50, respectively,after 24 h and 48 h, as compared to the IC50 of ponatinib. Lower combined concentrations showed greater synergism(combination index<1) with a higher ponatinib dose reduction index. Moreover,ponatinib plus gossypol induced morphological changes in HCT-116and Caco-2 cells, increased beclin-1 and caspase-3, and decreased FGF19, FGFR4, Bcl-2 and p-Akt as compared to treatment with drugs alone.Conclusions: Gossypol enhances ponatinib’s anticancer effects against colorectal cancer cells through antiproliferative, apoptotic,and autophagic mechanisms. This may open the way for the future use of ponatinib at lower doses with gossypol as a potentially safer targeted strategy for colorectal cancer treatment.