Curcumin Sensitizes Colorectal Cancer Cells to TRAIL-Mediated Apoptosis

Colorectal cancer (CRC) remains a major clinical challenge due to resistance to conventional cell death-inducing therapies. TRAIL selectively induces apoptosis in cancer cells via death receptors, but its effectiveness in preclinical models is limited by tumor resistance mechanisms. Curcumin, a natural polyphenol, modulates multiple survival and apoptotic pathways and has been proposed as a sensitizing agent to overcome TRAIL resistance. Here, we investigated the combinatorial effects of TRAIL and curcumin in the HCT116 colorectal cancer cell model. Cells were treated with TRAIL, curcumin, or their combination for 24 and 48 h, evaluating apoptosis, viability, and underlying mechanisms. Curcumin significantly enhanced TRAIL-induced apoptosis (p < 0.0001) and further reduced MTT-derived metabolic activity (p < 0.01) compared with TRAIL treatment alone. This effect remained evident after 48 h, although the stability and persistence of TRAIL activity were not directly assessed. Mechanistically, combined treatment enhanced PARP cleavage, γ-H2AX phosphorylation, and BAX and Caspase-3 cleavage, while downregulating anti-apoptotic IAP family members. Notably, cotreatment also promoted pyroptosis, shown by characteristic morphological changes (p < 0.0001) and increased Gasdermin-E cleavage. These findings indicate that curcumin sensitizes CRC cells to TRAIL by engaging both apoptotic and pyroptotic pathways, suggesting a potential approach to counteract both TRAIL and multidrug resistance in colorectal cancer.