School of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China.
Cancer Lett. 2010 Jul 28;293(2):158-66. doi: 10.1016/j.canlet.2010.01.005. Epub 2010 Feb 6.
The present data showed that sunitinib potentiated the in vitro and in vivo anticancer capabilities of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), also known as Apo2 ligand. Interactions between sunitinib and TRAIL were examined in colon cancer SW620 cells and lung cancer 95-D cells. The average combination index (CI) values of the anti-proliferation abilities on each cancer cell line were less than 1.0, demonstrating the synergism of the combination of sunitinib and TRAIL. Western blot experiments indicated that TRAIL and sunitinib synergistically enhanced apoptosis by simultaneously activating the extrinsic and intrinsic pathways. The decrease in the expression levels of anti-apoptotic proteins cFLIP, XIAP and Mcl-1 were probably involved in this apoptosis enhancement. Furthermore, treatment of colon cancer SW620-bearing nude mice with sunitinib plus TRAIL resulted in more significant tumor growth inhibition (52.8%), comparing with the moderate inhibition in TRAIL-treated (35.3%) or sunitinib-treated groups (26.7%) (p<0.05). These results indicate that the combination of TRAIL with sunitinib seems highly encouraging and warrants further investigation in a clinical setting.
本研究数据表明，舒尼替尼可增强肿瘤坏死因子相关凋亡诱导配体（TRAIL），又称 Apo2 配体的体外和体内抗癌能力。在结肠癌 SW620 细胞和肺癌 95-D 细胞中检测了舒尼替尼与 TRAIL 之间的相互作用。每种癌细胞系的抗增殖能力的平均合并指数（CI）值均小于 1.0，表明舒尼替尼和 TRAIL 的联合具有协同作用。Western blot 实验表明，TRAIL 和舒尼替尼通过同时激活外源性和内源性途径协同增强细胞凋亡。抗凋亡蛋白 cFLIP、XIAP 和 Mcl-1 的表达水平降低可能参与了这种凋亡增强。此外，舒尼替尼联合 TRAIL 治疗结肠癌 SW620 荷瘤裸鼠可导致更显著的肿瘤生长抑制（52.8%），而 TRAIL 治疗组（35.3%）或舒尼替尼治疗组（26.7%）的抑制作用中等（p<0.05）。这些结果表明，TRAIL 与舒尼替尼联合应用具有很大的前景，值得在临床环境中进一步研究。
