研究olapairb在小細胞肺癌的抗癌效果

Abstract

小細胞肺癌(SCLC)是極具侵略性的惡性腫瘤，生長快速、早期轉移和產生抗藥性等特性，化療藥物僅有一線的cisplatin加etoposide以及二線的topotecan，而且目前還沒有標靶藥物可以使用。因此發展新的醫療策略對小細胞肺癌患者是十分迫切的。Poly (ADP-ribose) polymerase(PARP) 是一類在細胞核中負責參與染色體修復的聚合酶，許多研究都證明癌細胞會大量表現PARP，包含小細胞肺癌。因此在這份研究中我們的目的是要探討PARP的抑制物Olaparib，對H209及H146兩株小細胞肺癌細胞的抗癌效果。我們的實驗結果顯示Olaparib可以抑制H209和H146細胞生長、並使細胞週期停滯在S及G2/M階段、以及促進細胞走向細胞凋亡(apoptosis)。細胞訊號傳遞路徑的結果顯示，Olaparib會抑制H209及H146的PARP以及細胞生長相關蛋白質的表現量。而在異體移植人類小細胞肺癌的免疫缺陷裸鼠動物模式中Olaparib亦能有效的抑制腫瘤的生長。我們更進一步將Olaparib與現有的化療藥物(cisplatin或etoposide)做合併測試，我們發現Olaparib合併化療藥物可以更有效的抑制小細胞肺癌細胞的生長並促進細胞凋亡產生。最後總結細胞毒殺性，及細胞週期分析，分子傳遞路徑，還有動物實驗結果指出，Olaparib在治療小細胞肺癌方面可能是一種很有潛力的標靶藥物。

Small cell lung cancer (SCLC) is highly aggressive and novel therapeutic strategies are urgently needed. Poly (ADP-ribose) polymerases (PARP) are proteins responsible for cellular processes including DNA repair and programmed cell death. Several studies have demonstrated that PARP inhibition is a promising in cancer treatments. Olaparib, AZD2281, is one of PARP inhibitor which has been approved of its use in advanced ovarian cancer and studied in several clinical trials. However, the cytotoxicity of olaparib in SCLC remains unelucidated. The aim of this study is to explore the anticancer activity of olaparib in SCLC cell lines and xenografts, by performing assays to assess cell proliferation, cell-cycle progression, apoptosis and signaling molecule expression. Furthermore, the enhanced efficacy of olaparib in combination with chemotherapeutic agents cisplatin or etoposide was investigated. Our results showed that olaparib significantly inhibited cell viability, induced programmed cell death, and arrested cell-cycle in S and G2/M phase on SCLC cells in a dose-dependent manner. In addition, the combinations of olaparib and cisplatin or etoposide demonstrated enhanced cytotoxicity by inhibiting cell viability and inducing apoptosis in H209 cells. The in vivo study demonstrated that olaparib was effective in reducing tumor growth in H209 xenografts. In summary, we have identified that the olaparib exerts potent anticancer activity as single agent and promotes anticancer efficacy in combined therapy in SCLC, and the results from our study may provide a potential therapeutic strategy for SCLC patients.