Department of Urology, University of Iowa, 375 Newton Road, Iowa City, IA 52242-1089, USA.
Apoptosis. 2011 Jan;16(1):13-26. doi: 10.1007/s10495-010-0535-3.
Urothelial carcinoma of the bladder accounts for approximately 5% of all cancer deaths in humans. The large majority of bladder tumors are non-muscle invasive at diagnosis, but even after local surgical therapy there is a high rate of local tumor recurrence and progression. Current treatments extend time to recurrence but do not significantly alter disease survival. The objective of the present study was to investigate the tumoricidal potential of combining the apoptosis-inducing protein TNF-related apoptosis-inducing ligand (TRAIL) with a small molecule inhibitor of apoptosis proteins (IAP) antagonist to interfere with intracellular regulators of apoptosis in human bladder tumor cells. Our results demonstrate that the IAP antagonist Compound A exhibits high binding affinity to the XIAP BIR3 domain. When Compound A was used at nontoxic concentrations in combination with TRAIL, there was a significant increase in the sensitivity of TRAIL-sensitive and TRAIL-resistant bladder tumor lines to TRAIL-mediated apoptosis. In addition, modulation of TRAIL sensitivity in the TRAIL-resistant bladder tumor cell line T24 with Compound A was reciprocated by XIAP small interfering RNA-mediated suppression of XIAP expression, suggesting the importance of XIAP-mediated resistance to TRAIL in these cells. These results suggest the potential of combining Compound A with TRAIL as an alternative therapy for bladder cancer.
膀胱癌占人类所有癌症死亡人数的约 5%。大多数膀胱肿瘤在诊断时是非肌肉浸润性的，但即使经过局部手术治疗，仍有很高的局部肿瘤复发和进展率。目前的治疗方法延长了复发时间，但并没有显著改变疾病的生存。本研究的目的是研究联合凋亡诱导蛋白 TNF 相关凋亡诱导配体（TRAIL）与凋亡蛋白抑制剂（IAP）拮抗剂的小分子来干扰人膀胱肿瘤细胞内凋亡的内源性调节因子的杀肿瘤潜力。我们的结果表明，IAP 拮抗剂化合物 A 对 XIAP BIR3 结构域具有高结合亲和力。当化合物 A 在非毒性浓度下与 TRAIL 联合使用时，TRAIL 敏感和 TRAIL 耐药膀胱肿瘤系对 TRAIL 介导的凋亡的敏感性显著增加。此外，用化合物 A 对 TRAIL 耐药膀胱肿瘤细胞系 T24 进行 TRAIL 敏感性的调节，通过 XIAP 小干扰 RNA 抑制 XIAP 表达得到了逆转，这表明 XIAP 介导的 TRAIL 耐药在这些细胞中很重要。这些结果表明，将化合物 A 与 TRAIL 联合作为膀胱癌的替代治疗具有潜力。
