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Cancer-specific enhancement of cisplatin-induced cytotoxicity with triptolide through an interaction of inactivated glycogen synthase kinase-3β with p53

Oncogene volume 27, pages 4603–4614 (2008)Cite this article

Abstract

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-3β (GSK3β), which was inactivated by protein kinase C (PKC). This modulation of the PKC-GSK3β 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.

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Authors and Affiliations

  1. Department of Urology, Graduate School of Medicine, Kyoto University, Kyoto, Japan

    Y Matsui, J Watanabe, T Kamoto, O Ogawa & H Nishiyama

  2. Department of Genomic Medical Sciences, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Japan

    M Ikegawa

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  1. Y Matsui
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  2. J Watanabe
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  3. M Ikegawa
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  4. T Kamoto
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  5. O Ogawa
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  6. H Nishiyama
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Correspondence to O Ogawa.

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Supplementary Information accompanies the paper on the Oncogene website (http://www.nature.com/onc).

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Matsui, Y., Watanabe, J., Ikegawa, M. et al. Cancer-specific enhancement of cisplatin-induced cytotoxicity with triptolide through an interaction of inactivated glycogen synthase kinase-3β with p53. Oncogene 27, 4603–4614 (2008). https://doi.org/10.1038/onc.2008.89

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