Presented October 25th - 28th, 2007 at the 2007 Urological Research Society (URS) Meeting - Napa, California

Objective: In the present study, we investigated the usefulness of p21 attenuating therapy using triptolide, an oxygenated diterpene derived from a Chinese herb, to enhance cytotoxicity of cisplatin (CDDP) in urothelial cancer cells

Methods: We screened several bladder cancer cell lines for the synergic effect of triptolide with cisplatin. Then, in bladder cancer cell lines showing synergic effect, the molecular mechanisms of the change of cisplatin-induced cytotoxicity by triptolide were evaluated. To evaluate the possibility of clinical use, monitoring of mouse xenograft model with subcutaneous injection of RT112-luc (RT112 stable transfectants with luciferase gene) by in vivo imaging system (IVIS) were used.

Results: By combination treatment with CDDP, triptolide enhanced its cytotoxicity in bladder cancer cell lines with wild-type p53. In RT112, combination treatment of triptolide and CDDP suppressed p53 transcriptional activity, and simultaneously, induced c-Jun N-terminal kinase (JNK) phosphorylation and Bax activation. As the synergic effect was suppressed by SP600125, a specific JNK inhibitor, or p21 shRNA transfection, JNK phosphorylation induced by the suppression of p21 was onsidered the main apoptotic pathway. Furthermore, we demonstrated that inhibitory ser-9 phosphorylation on glycogen synthase kinase-3β (p-Ser-9 GSK3β) interacting with p53 was responsible for the modulation of p53 transcriptional activity by triptolide. A mouse xenograft model showed the effectiveness of the combination use of triptolide and CDDP.

Conclusions: We expect that cancer-specific p21 attenuating therapy using triptolide has the possibility to break through the resistance to CDDP-based conventional chemotherapy in urothelial cancer

Authors: Matsui Y and Ogawa O

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