克服尿路上皮癌化學治療抗藥性的治療策略

許富順、林家齊¹、黃國皓²

台北市立聯合醫院陽明院區 泌尿科；¹台大醫院 腫瘤部；²台大醫院 泌尿部

New Treatment Strategies for Overcoming the Chemoresistance of Urothelial Carcinoma

Fu-Shun Hsu, Chia-Chi Lin¹, Kuo-How Huang²

Department of Urology, Yangming Branch, Taipei City Hospital, Taipei, Taiwan;
Department of Oncology¹ and Urology², National Taiwan University Hospital, Taipei, Taiwan

Purpose: The overall response rate to treatment of metastatic urothelical carcinoma (UC) with first-line regimen, including cisplatin and gemcitabine, remains at 50%–60%. Second-line chemotherapy, including paclitaxel and vinflunine, have been developed for advanced and metastatic UC. Most patients experience chemoresistance, however, which leads to disease relapse. Therefore, the development of innovative UC treatments that address chemoresistance is urgently needed.

Materials and Methods: We evaluated the antitumor effects of trichostatin A (TSA), an antifungal antibiotic that inhibits histone deacetylases (HDACs), alone or in combination with other chemotherapeutic agents, including cisplatin, gemcitabine, doxorubicin, and paclitaxel, for the treatment of human UC. Furthermore, we investigated the antitumor effect of the deubiquitylating enzyme inhibitor PR-619 in cisplatin-resistant bladder UC cells.

Results: Our results showed that TSA co-treatment with any one of the four chemotherapeutic agents induced synergistic cytotoxicity and concomitantly suppressed chemotherapeutic drug-induced activation of the mitogen-activated protein kinase (MAPK) / extracellular signal-regulated kinase (ERK) pathway. These observations were confirmed in a xenograft nude mouse model. The activated MAPK/ERK pathway was also observed in human bladder specimens from chemoresistant UC patients. These findings support that TSA elicited a synergistic cytotoxic response in combination with chemotherapy by targeting the MAPK/ERK pathway. PR-619 was found to enhance the cytotoxic and apoptotic effects of cisplatin in cisplatin-resistant T24/R cells. Mitigated cisplatin chemoresistance was associated with concurrent suppression of c-Myc expression in T24/R cells. Moreover, c-Myc expression was upregulated in human bladder specimens from chemoresistant UC patients. In the xenograft nude mouse model, PR-619 also enhanced the antitumor effects of cisplatin.

Conclusions: Our findings suggest that, by disrupting the c-Myc pathway, therapeutic strategies can prevent UC chemoresistance through the combined use of chemotherapeutic agents and PR-619. Our results substantiate the potential clinical applications of histone deacetylase inhibitors and deubiquitinating enzyme inhibitors, and the importance of identifying and developing chemosensitizers that improve the therapeutic efficacy of treatments for chemoresistant UC cells.