研究2-deoxy-glucose對人類小細胞肺癌的抗癌效果

Abstract

近年來，小細胞肺癌(SCLC)已成為想當重要的癌症之一，它是具有非常高侵略性的惡性腫瘤，以及早期轉移生長快速、生長快速和產生抗藥性等特性，在臨床上的化療藥物僅有一線的cisplatin加etoposide以及二線的topotecan，到目前尚未有標靶藥物可以治療。因此如何找到有效治療小細胞肺癌的方法，就成為科學家重要的研究項目之一。醣解循環一直以來都是研究癌症的學者很重要的一條路徑，也有許多研究指出癌細胞為了要迅速的生長，在醣類的需求比起正常細胞要高很多。因此在這份研究中我們主要是探討Glycolysis 的抑制物2-deoxy-glucose (2DG)，對H146和H209兩株小細胞肺癌細胞株的抗癌效果。我們的研究結果顯示2DG可以抑制H146和H209細胞生長，並使細胞週期停滯在Sub-G1時期以及促使細胞走向細胞凋亡的路徑。細胞訊號傳遞路徑的研究結果顯示，2DG會抑制小細胞肺癌細胞的生長相關蛋白和PARP的表現量。再者我們將2DG與現有的一線化療用藥(Etoposide和Cisplatin)去做合併治療，我們也發現2DG合併化療用藥可有效的抑制小細胞肺癌的生長以及促進細胞凋亡的產生。最後合併了細胞週期、分子訊號傳遞路徑、細胞毒殺性測試等實驗，我們研究結果指出2DG在治療小細胞肺癌的方面可能會是很有潛力的標靶用藥。

Small cell lung cancer (SCLC) is a devastating disease and a major therapeutic burden with poor survival rates. Chemotherapy remains the cornerstone of treatment for both limited-stage and extensive-stage SCLC. Cancer cells display high rates of aerobic glycolysis in comparison with their non-transformed counterparts. So, targeting glycolysis for cancer treatment has been explored previously as a therapeutic approach. The aim of this study is to explore the anticancer activity of a 2-deoxy-glucose in SCLC cell lines and xenografts, by performing assays to assess cell proliferation, apoptosis, signaling pathways, and cell cycle progression. Furthermore, the enhanced efficacy of the 2-deoxy-glucose in combination with either cisplatin or etoposide has been investigated. Our preliminary results showed that the 2-deoxy-glucose dose-dependently inhibited cell viability and induced programmed-cell death in SCLC cells. The 2-deoxy-glucose also significantly affected critical signaling pathways (AKT, ERK, S6). In combination treatments, the 2-deoxy-glucose plus cisplatin or etoposide has shown significant anti-proliferative activity as compared with single agent alone. In the future, we will investigate whether the 2-deoxy-glucose has an impact in cell cycle progression. In addition, we will assess the anti-tumor activity of the 2-deoxy-glucose alone or in combination with chemotherapeutic agent in H209 xenografted nude mice. In summary, results from our studies have suggested that 2-deoxy-glucose could serve as a promising class of anti-tumor agent for future SCLC treatments.