Zeng Fu-Yue, Cui Jimmy, Liu Lingling, Chen Taosheng
Department of Chemical Biology and Therapeutics, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
Cancer Lett. 2009 Nov 1;284(2):157-64. doi: 10.1016/j.canlet.2009.04.016. Epub 2009 May 12.
Patients with alveolar rhabdomyosarcoma (ARMS) have poorer response to conventional chemotherapy and lower survival rates than those with embryonal RMS (ERMS). By high-throughput screening, we identified camptothecin as an ARMS-selective inhibitor. Camptothecin more efficiently inhibited proliferation and induced apoptosis in Rh30 (ARMS) than RD (ERMS) cells. Ectopic expression of the PAX3-FKHR (PF) fusion protein in RD cells significantly increased sensitivity, whereas siRNA knockdown of PF decreased sensitivity of Rh30 cells to camptothecin. The sensitization required a transcriptionally active PF, and camptothecin downregulated levels of PF protein. These findings suggest that it is feasible to develop agents that preferentially block the growth of ARMS.
与胚胎型横纹肌肉瘤(ERMS)患者相比,肺泡型横纹肌肉瘤(ARMS)患者对传统化疗的反应较差,生存率较低。通过高通量筛选,我们确定喜树碱是一种ARMS选择性抑制剂。喜树碱对Rh30(ARMS)细胞的增殖抑制和诱导凋亡作用比RD(ERMS)细胞更有效。RD细胞中PAX3-FKHR(PF)融合蛋白的异位表达显著增加了敏感性,而PF的siRNA敲低则降低了Rh30细胞对喜树碱的敏感性。这种致敏作用需要转录活性的PF,并且喜树碱下调了PF蛋白的水平。这些发现表明,开发优先阻断ARMS生长的药物是可行的。