Synergic anti-tumor effect of pterostilbene, an inhibitor of type I insulin-like growth factor receptor, and trastuzumab against HER2-overexpressing bladder cancer cells

紫檀芪，一個抑制類胰島素生長因子1受體的藥物，對於合併使用賀癌平治療HER-2過度表現的膀胱癌上之成效的協同抗癌作用

陳忠賢(Chung-Hsien Chen) ； 吳振宇(Chen-Yu Wu) ； 陳毓騏(Yu-Chi Chen) ； 魏宗德(Tzong-Der Way) ； 林嘉祥(Victor C. Lin)

《輔仁醫學期刊》 15卷4期 (2017/12) Pp. 191-202

https://doi.org/10.3966/181020932017121504003

摘要

Background and purpose: Stilbene has been extensively investigated in varied fields including being anticancer agents. In this study, we proposed pterostilbene, a more potent compound of stilbenes, serve as a novel type I insulin-like growth factor receptor inhibitor (IGR- 1R inhibitor), and have synergic effect on bladder cancer cells. Methods: We treated bladder cancer cell lines with pterostilbene and utilized western blot analyses cell proliferation assays and flow cytometry to analyze the effect of pterostilbene on bladder cancer cell proliferation and cell cycle. We analyzed on perostilbene on IGF-1R of bladder cancer cell and also tried to explore the downward pathway. In addition, we used Chou and Talalay's combination index (CI) algorithm to exam the efficacy of pterostilbene in potentiating the effects of trastuzumab on Human epidermal growth factor receptor2-overexpressing (HER2) overexpressing bladder cancer cells. Results: Pterostilbene was shown to provoke a dose-dependent increase in the number of cells in G0/G1 phase of the cell cycle, and a decrease in the G2/M and S phases. Moreover, pterostilbene induced an increase in p27 expression, together with a decrease in p21 expression. Additionally, it led to a decrease in phosphorylated AKT levels in HER2-overexpressing T24 cells, and induced the apoptosis of T24 cells. A clear synergistic effect was obtained when the cells were treated with pterostilbene in combination with trastuzumab. Conclusion: Pterostilbene represents a novel IGF-1R inhibitor, which acts synergistically with trastuzumab, inhibiting the proliferation of HER2-overexpressing bladder cancer cells. These results demonstrate that anti-IGF-1R agent, such as pterostilbene, may be effectively combined with trastuzumab in order to achieve a more effective treatment of trastuzumab-resistant bladder cancers.

關鍵字

bladder cancer ； type I insulin-like growth factor receptor ； trastuzumab ； pterostilbene

並列摘要

背景及目的：二苯乙烯（stilbene）在各面都被廣泛的研究，包括對抗惡性腫瘤的能力。此研究希望證明紫檀芪（pterostilbene），一個強力的二苯乙烯，可做為新一代類胰島素生長因子1受體抑制劑並且對於膀胱癌細胞有毒殺的加乘作用。方法：我們使用紫檀芪治療膀胱癌細胞，並且利用西方墨點法分析細胞增殖試驗以及利用流式細胞技術分析癌細胞之增生及細胞週期。我們分析紫檀芪在類胰島素生長因子1受體膀胱癌的細胞並嘗試找尋下游路徑。周塔氏藥物合併指數（Chou and Talalay's combination index）被用來檢驗紫檀芪對於賀癌平（trastuzumab）在治療HER-2過度表現的膀胱癌上之成效影響。結果：在此試驗中，紫檀芪顯現出隨著劑量上升可以激發G0/G1期細胞的數量上升並且降低G2/M以及S期的細胞數量。更甚者，紫檀芪可以引發p27的表現上升以及降低p21的表現。除此之外，此藥物更能下降在HER-2過度表現的T24細胞中磷酸化蛋白激酵素（Akt）的濃度，藉此引發其凋亡。紫檀芪合併賀癌平治療膀胱癌的協同作用在此試驗中被明顯地觀察到。結論：紫檀芪可作為新一代的類胰島素生長因子1受體抑制劑並且可以對於賀癌平在抑制HER-2過度表現的膀胱癌細胞增生上有協同作用。這個結果可以驗證像紫檀芪這類抗類胰島素生長因子1受體之藥物，可以與賀癌平合併使用達到對其有抗性之膀胱癌有更好的療效。

並列關鍵字

膀胱癌 ； 類胰島素生長因子1受體 ； 賀癌平 ； 紫檀芪