熱休克蛋白90抑制劑於小細胞肺癌的抗癌效果之研究

Abstract

肺癌是癌症所導致的死亡中最常見的一種，其中小細胞肺癌相較於非小細胞肺癌是屬於較具侵略性的，其生長速度快，以及有早期轉移和抗藥性等問題的存在，因此在治療上是屬於較為棘手的一類癌症。至今，化學治療依然是最主要的臨床治療方法。因此，臨床上我們急需發展出一個新型的治療策略。在本研究中，我們將研究熱休克蛋白90 (HSP90) 抑制劑對於小細胞肺癌的抗癌效果。我們選用alvespimycin (17-DMAG) 作為熱休克蛋白90抑制劑，17-DMAG是benzoquinone ansamycin的衍生物，可與熱休克蛋白90結合而導致熱休克蛋白90 被抑制，進而影響熱休克蛋白90的客戶蛋白，最後致使客戶蛋白被降解，藉此達到抗癌的效果。我們研究的結果顯示，17-DMAG可有效的抑制小細胞肺癌的生長及誘使癌細胞走向凋亡。除此之外，我們也觀察到小細胞肺癌的細胞週期會被17-DMAG調控，使得細胞週期滯留在G2/M 期。透過訊息傳遞路徑的研究，結果顯示17-DMAG會影響Akt/mTOR 和STAT3訊息傳遞路徑的等相關蛋白。同時，在研究中也發現17-DMAG與臨床化療藥物配合使用後有更好的抑制癌細胞生長與促進癌細胞凋亡的效果。總結，我們的研究結果顯示熱休克蛋白90抑制劑17-DMAG有潛力作為小細胞肺癌的標靶治療藥物。

Lung cancer has become the common cause of cancer-related death worldwide. The small cell lung cancer (SCLC) is a highly aggressive tumor with rapidly growth, early dissemination and development of drug resistance. To date, the chemotherapy remains the cornerstone of treatment in SCLC patients. Therefore, the new therapeutic strategies for SCLC are urgently needed. In this study, we investigated the anti-cancer effects of heat shock protein 90 (HSP90) inhibitor in SCLC. The HSP90 inhibitor alvespimycin (17-DMAG) is a derivative of benzoquinone ansamycin. It binds specifically to the HSP90 and alters its client proteins. Our results showed that the HSP90 inhibitor 17-DMAG enhanced cell toxicity and induced cell apoptosis in the H146, H1688, and H209 SCLC cell lines. Furthermore, the 17-DMAG inhibited cell proliferation through the induction of G2/M arrest in SCLC cell lines. In the analysis of the signaling transduction pathways, 17-DMAG treatments affected the Akt/mTOR and STAT3 signaling molecules in SCLC cells. In addition, cotreatment with 17-DMAG enhances premetrexed or etoposide mediated cell toxicity and apoptosis.. In summary, our results suggest that HSP90 inhibitor 17-DMAG may be a potential target therapeutic agent in the treatment of SCLC.