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

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-3b (GSK3b), which was inactivated by protein kinase C (PKC). This modulation of the PKC-GSK3b 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.

Triptolide (TPL) Inhibits Global Transcription by Inducing Proteasome-Dependent Degradation of RNA Polymerase II (Pol II)

“…It has been reported that its pro-apoptotic activity is due to modulation of apoptosis-activating proteins [28], [29] and is partially dependent on calcium [30]. It was found that cancer cell-specific enhancement of cisplatin-induced cytotoxicity with TPL was through an interaction of inactivated glycogen synthase kinase-3 with p53 [31]. It was also reported that TPL suppressed NF-κB, AP-1, NFAT, and HSF1 transactivation, and the inhibition of NF-κB and HSF1 was at a step following their DNA binding [7], [32], [33].…”

Triptolide Cooperates With Cisplatin to Induce Apoptosis in Gemcitabine-Resistant Pancreatic Cancer

“…Our results, showing that TPL combined with DDP has a strong synergic effect in gemcitabine-resistant pancreatic cancer cells, again confirm the role of TPL as a chemotherapy sensitizer and concur with those obtained in urothelial cancer cells. 38 In this article, we first report that TPL, by blocking the expression of HSP27, acts in synergy with DDP to induce apoptosis in human gemcitabine-resistant pancreatic carcinoma.…”

p53 and chemosensitivity in bladder cancer

“…48 Also, triptolide (PG490), a diterpenoid triepoxide derived from the herb Tripterygium wilfordii, enhanced the cytotoxicity of cisplatin through c-Jun N-terminal kinase (JNK) activation by the suppression of the p53-p21 pathway in urogenital cancer cells. 49 These fi ndings indicate that the induction of p53-p21 in malignant cells, at least in UC, has the possibility to suppress the apoptotic process, and conversely, that the attenuation of p21 expression may make genotoxic chemotherapeutic agents more effective by subverting the normal repair process. 50 …”