(嘉基醫院+中正大學)Cyproheptadine(抗組織胺藥) 具抑制膀胱癌潛力

感冒藥能治癌？中正大學與嘉基新研究登上國際期刊 2017-11-22〔記者曾迺強／嘉義報導〕中正大學生物醫學科學系與嘉義基督教醫院研究團隊歷經5年研究，證實市面上常見的抗組織胺感冒藥「佩你安」，能抑制膀胱癌腫瘤生長，更找出受藥物影響的關鍵基因，只要觀察該基因的活躍程度，能判斷膀胱癌病人的癒後狀況，研究成果登上英國最新一期「Oncogene」（癌症基因）期刊。中正大學與嘉義基督教醫院今天在中正大學理學院辦「佩你安抗癌新療法躍登國際知名癌症期刊《Oncogene》」記者會，宣布這項研究成果。嘉義基督教醫院肝膽腸胃科醫師酆裕民說，「佩你安」是30年前就問世的感冒過敏用藥，10年來發現有2例肝癌病人服用「佩你安」後，腫瘤竟完全消失，進一步研究該藥物與癌細胞的研究。嘉義基督教醫院泌尿外科醫師沈正煌、周詠欽等人聽聞，主動與中正大學組成研究團隊，醫院提供膀胱病患的檢體與臨床資料，中正大學團隊則驗證抗組織胺藥物「佩你安」對膀胱癌的影響。中正大學生物醫學科學系教授陳永恩說，研究團隊針對罹患惡性膀胱癌的小鼠投藥試驗，發現癌症腫瘤的因服用藥物而縮小一半，證實「佩你安」確能抑制膀胱癌腫瘤生長，進而找到抑制膀胱癌的關鍵基因。陳永恩說，「ANGPTL4」基因是毒殺膀胱癌的重要基因，在癌細胞中被關閉，使用「佩你安」後，ANGPTL4基因又「活」了起來；醫師周詠欽指出，若病人體內ANGPTL4基因較活躍，能控制癌症向外擴散，不易復發，提高病人的存活率。中正大學研究團隊正規劃申請人體臨床試驗，讓易復發或已轉移第3、4期的膀胱癌病人服用抗組織胺藥物；嘉義基督教醫院院長陳誠仁說，此藥物尚未進行人體試驗，民眾未經醫師指示，勿隨意服用。

Epigenetic silencing of the dual-role signal mediator, ANGPTL4 in tumor tissues and its overexpression in the urothelial carcinoma microenvironment Oncogene, 16 October 2017/ Urothelial carcinoma (UC) carcinogenesis has been hypothesized to occur through epigenetic repression of tumor-suppressor genes (TSGs). By quantitative real-time polymerase chain reaction array, we found that one potential TSG, angiopoietin-like 4 (ANGPTL4), was expressed at very low levels in all bladder cancer cell lines we examined. Previous studies had demonstrated that ANGPTL4 is highly expressed in some cancers, but downregulated, by DNA methylation, in others. Consequently, owing to these seemingly conflicting functions in distinct cancers, the precise role of ANGPTL4 in the etiology of UC remains unclear. In this study, using methylation-specific PCR and bisulfite pyrosequencing, we show that ANGPTL4 is transcriptionally repressed by DNA methylation in UC cell lines and primary tumor samples, as compared with adjacent noncancerous bladder epithelium. Functional studies further demonstrated that ectopic expression of ANGPTL4 potently suppressed UC cell proliferation, monolayer colony formation in vitro, and invasion, migration, and xenograft formation in vivo. Surprisingly, circulating ANGPTL4 was significantly higher in plasma samples from UC patients than normal control, suggesting it might be secreted from other cell types. Interestingly, our data also indicated that exogenous cANGPTL4 could promote cell proliferation and cell migration via activation of signaling through the Erk/focal adhesion kinase axis. We further confirmed that mouse xenograft tumor growth could be promoted by administration of exogenous cANGPTL4. Finally, immunohistochemistry demonstrated that ANGPTL4 was downregulated in tumor cells but overexpressed in tumor adjacent stromal tissues of muscle-invasive UC tissue samples. In conclusion, our data support dual roles for ANGPTL4 in UC progression, either as a tumor suppressor or oncogene, in response to microenvironmental context.

Cyproheptadine exhibits antitumor activity in urothelial carcinoma cells by targeting GSK3β to suppress mTOR and β-catenin signaling pathways. Cancer Lett. 2016 Jan 1;370(1):56-65. Cyproheptadine, a serotonin antagonist, has recently been reported to function as a novel therapeutic agent by inhibiting PI3K/AKT signaling in several human cancers. However, the therapeutic effect of cyproheptadine in urothelial carcinoma (UC) has never been explored. In this study, we determined the effect of cyproheptadine on the growth of five human UC cell lines and an in vivo xenograft model. The results showed that cyproheptadine exerted an inhibitory effect on the proliferation of UC cells both in vitro and in vivo. Cyproheptadine also induced cell cycle arrest in the G1 phase, subsequently followed by apoptosis and necrosis. The underlying mechanisms of cell cycle arrest were associated with the reduction of c-Myc, induction of p21 and p27, and the stabilization of Rb expression. In addition, the suppression of the GSK3β/TSC2/mTOR pathway and deregulation of the GSK3β/β-catenin signaling were observed in cyproheptadine-treated UC cells. Furthermore, cyproheptadine-induced apoptosis was associated with ANGPTL4 expression followed by activation of caspase3 and PARP in UC cells. Our experimental results provide evidence that cyproheptadine is a suitable therapeutic agent for the treatment of UC.

治療膀胱癌新發現 醫、校揭「抑制腫瘤」生長關鍵 2017年11月22日 13:29 中時 呂妍庭 中正大學生物醫學科學系與嘉義基督教醫院研究團隊歷經5年研究，證實市面上常見的抗組織胺感冒藥能有效抑制膀胱癌腫瘤生長，並找出受藥物影響的關鍵基因，而研究源起，是嘉基胃腸肝膽科醫師酆裕民觀察到同時有服用「佩你安」的肝癌病人，腫瘤有縮小甚至消失現象，目前該研究成果已發表在國際知名癌症期刊《Oncogene》上，未來將進行人體臨床試驗。酆裕民表示，他觀察了10年，並比對52位肝癌病人服藥結果，發現「佩你安」似乎對肝腫瘤有一定療效，嘉基泌尿外科醫師沈正煌、周詠欽聽聞此事，主動和中正組成研究團隊，由院方提供膀胱病患的檢體與臨床資料，交由中正著手驗證抗組織胺藥物「佩你安」對膀胱癌的影響。陳永恩說，「佩你安」是2、30年前就存在的常見感冒過敏藥，在5年研究過程中，團隊首先針對罹患惡性膀胱癌的小鼠進行投藥試驗，發現癌症腫瘤的大小因服用藥物而縮小約50％，證實「佩你安」抗組織胺藥物的確能抑制膀胱癌的腫瘤生長，之後更進一步找到抑制膀胱癌的關鍵基因。陳永恩說，ANGPTL4基因是毒殺膀胱癌的重要基因，在癌細胞中是被關閉的，但在使用藥物後，讓ANGPTL4基因又「活」了起來，成為醫師判斷膀胱癌病人病情發展及癒後狀況的參考依據。周詠欽醫師表示，膀胱癌最擔心的就是復發，如果病人體內的ANGPTL4基因是活躍的，將可控制癌症向外擴散，且較不易復發，提高病人的存活率。這項重大發現近日已獲《Oncogene》刊登，而中正研究團隊正規畫申請人體臨床試驗，未來將嘗試讓易復發或已轉移第3、4期的膀胱癌病人服用抗組織胺藥物。(中時)