Tumor necrosis factor‑related apoptosis‑inducing ligand as a therapeutic option in urothelial cancer cells with acquired resistance against first‑line chemotherapy

Patients with urothelial carcinoma frequently fail to respond to firstline chemotherapy using cisplatin and gemcitabine due to development of resistant tumor cells. The aim of the present study was to investigate whether an alternative treatment with tumor necrosis factorrelated apoptosisinducing ligand (TRAIL) that induces tumor cell death via the extrinsic apoptotic pathway may be effective against chemotherapyresistant urothelial cancer cell lines. The viability of the urothelial cancer cell line RT112 and its chemotherapyadapted sublines was investigated by MTT assay. The expression of antiapoptotic proteins was determined by western blotting and the individual roles of cellular inhibitor of apoptosis protein (cIAP)1, cIAP2, xlinked inhibitor of apoptosis protein (XIAP) and induced myeloid leukemia cell differentiation protein (Mcl1) were investigated by siRNAmediated depletion. In particular, the bladder cancer sublines that were resistant to gemcitabine and cisplatin were crossresistant to TRAIL. Resistant cells displayed upregulation of antiapoptotic molecules compared with the parental cell line. Treatment with the second mitochondrial activator of caspases (SMAC) mimetic LCL161 that antagonizes cIAP1, cIAP2 and XIAP resensitized chemoresistant cells to TRAIL. The resensitization of tumor cells to TRAIL was confirmed by depletion of antiapoptotic proteins with siRNA. Collectively, the findings of the present study demonstrated that SMAC mimetic LCL161 increased the sensitivity of the parental cell line RT112 and chemotherapyresistant sublines to TRAIL, suggesting that inhibiting antiapoptotic molecules renders TRAIL therapy highly effective for chemotherapysensitive and resistant urothelial cancer cells.