使用黃酮類藥物來提升順鉑類化療藥物在尿路上皮癌的治療效果

Flavonoids as a Therapeutic Strategy to Enhance Cisplatin Chemosensitivity in Urothelial Cancer

李經家(Ching-Chia Li)

指導教授 ： 吳永昌

高雄醫學大學/醫學院/醫學研究所博士班/博士(2016年)

摘要

尿路上皮癌在泌尿科是極為重要的一種致命疾病，接受化學治療的病人對順鉑藥物(cisplatin)產生抗藥性是最大的致命原因。在多種癌症的研究中，ATR-Chk1路徑已經有諸多報告發表。但是在上泌尿道上皮癌中的相關研究卻鮮少被提及。此外 DNA損傷常與鉑類化療藥物之抗藥性產生有關; 然而克服鉑類化療藥物抗藥性之治療策略至今尚未確立。我們的研究證明使用ATR-Chk1 抑制劑WYC0209可以增強膀胱癌對順鉑的敏感性。在使用臨床檢體基因距陣資料分析發現，高度表現ATR膀胱癌腫瘤之病人對接受化學治療有較差的預後。進一步實驗發現使用藥理或基因操作方式抑制ATR可以增強順鉑的藥效，如使用WYC0209或siATR可以增加膀胱癌細胞內順鉑嵌合到DNA上的數量。同時我們也觀察到抑制ATR可降低細胞p-glycoprotein 表現。此外在動物模式上，合併處理順鉑與WYC0209展現出協同作用抑制膀胱癌腫瘤增生，也證明WYC0209在動物模式可以增強順鉑之藥效且可以降低腫瘤上p-glycoprotein表現。我們研究結果指出控制ATR-Chk1路徑可以增強順鉑藥物在治療尿路上皮癌的效果。

關鍵字

黃酮 ； 順鉑 ； 尿路上皮癌 ； 化學治療

並列摘要

Urothelial cancer is a very important lethal disease , chemoresistance is the main cause lead to death in patients with advanced urothelial cancer. DNA damage responses contribute to cisplatin resistance; however, therapeutic strategies to overcome cisplatin resistance have not yet been established. Here, we demonstrate that inhibition of ATR-Chk1 pathway with the potent inhibitor WYC0209 sensitizes bladder cancer cells to cisplatin. In the clinical microarray profile, high ATR expression is associated with poor prognosis in bladder cancer patients who receive chemotherapy. We show that pharmacological and genetic suppressing of ATR sensitized cells to cisplatin. Treatment with WYC0209 or siATR increased levels of cisplatin-DNA adducts, concomitant with decreased levels of p-glycoprotein expression. Additionally, Combinations of cisplatin and WYC0209 show synergistic activity against bladder cancer. Ultimately, WYC0209 enhanced the anti-tumor effects of cisplatin and suppressed p-glycoprotein expression in bladder cancer xenografts. These results indicate that inhibiting ATR-Chk1 activation with WYC0209 and suppresses p-glycoprotein expression and increases cisplatin activity in bladder cancer. Our findings collectively suggest that ATR-Chk1 is a target for improving the efficacy of cisplatin in bladder cancer.

並列關鍵字

flavonoids ； cisplatin ； chemotherapy ； urothelial carcinoma

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