Matsui Y, Watanabe J, Ikegawa M, Kamoto T, Ogawa O, Nishiyama H
Department of Urology, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
Oncogene. 2008 Jul 31;27(33):4603-14. doi: 10.1038/onc.2008.89. Epub 2008 Apr 7.
To improve conventional chemotherapeutic efficacy, a combination use of traditional medicines is effective but detailed mechanisms have been rarely elucidated. In the this study, we attempted to clarify how triptolide (PG490), an oxygenated diterpene derived from a Chinese herb, enhances the cisplatin (CDDP)-induced cytotoxicity in urothelial cancer cells. Our results showed that a combined CDDP/triptolide therapy induced apoptosis in urothelial cancer cell lines with wild-type p53, but not in those with mutant-type p53 or normal human urothelium. As the mechanism, triptolide suppressed CDDP-induced p53 transcriptional activity, leading to p21 attenuation, which promoted apoptosis via the activation of c-Jun N-terminal kinase (JNK) and Bax. We further demonstrated that the functional regulation of p53 by triptolide was mediated by an intranuclear association of p53 with glycogen synthase kinase-3beta (GSK3beta), which was inactivated by protein kinase C (PKC). This modulation of the PKC-GSK3beta axis by triptolide was observed in a cancer-specific manner. A mouse xenograft model also showed that a combined CDDP/triptolide therapy completely suppressed tumor growth without any side effects. We expect that cancer-specific enhancement of CDDP-induced cytotoxicity with triptolide may effectively overcome the resistance to a CDDP-based conventional chemotherapy as a treatment for urothelial cancer.
为提高传统化疗疗效，联合使用传统药物是有效的，但具体机制鲜有阐明。在本研究中，我们试图阐明雷公藤内酯醇（PG490），一种源自中药的氧化二萜，如何增强顺铂（CDDP）诱导的膀胱癌细胞的细胞毒性。我们的结果表明，联合使用CDDP/雷公藤内酯醇疗法可诱导具有野生型p53的膀胱癌细胞系发生凋亡，但对具有突变型p53的细胞系或正常人膀胱上皮细胞则无此作用。机制上，雷公藤内酯醇抑制CDDP诱导的p53转录活性，导致p21衰减，进而通过激活c-Jun氨基末端激酶（JNK）和Bax促进凋亡。我们进一步证明，雷公藤内酯醇对p53的功能调节是由p53与糖原合酶激酶-3β（GSK3β）在细胞核内的结合介导的，而GSK3β被蛋白激酶C（PKC）失活。雷公藤内酯醇对PKC-GSK3β轴的这种调节以癌症特异性方式观察到。小鼠异种移植模型也表明，联合使用CDDP/雷公藤内酯醇疗法可完全抑制肿瘤生长且无任何副作用。我们期望雷公藤内酯醇对CDDP诱导的细胞毒性的癌症特异性增强可有效克服对基于CDDP的传统化疗的耐药性，作为膀胱癌症的一种治疗方法。
