探討合併2-deoxyglucose與cisplatin/etoposide在小細胞肺癌的抗癌效果

Investigation on the anticancer effects of 2-deoxyglucose combined with cisplatin/etoposide in small cell lung cancer

彭乃恩(Nai-En Peng)

指導教授 ： 梁美智

國立交通大學/生物科技學院/分子醫學與生物工程研究所/碩士(2019年)

摘要

小細胞肺癌(Small cell lung cancer, SCLC)占整體肺癌病例的比例約為10-15%，與非小細胞肺癌(Non-small cell lung cancer, NSCLC)相比具有高度侵略性、早期轉移和治療後期容易產生抗藥性等的特性。目前治療小細胞肺癌以全身性的化學治療為主，儘管患者在接受第一線以合併Cisplatin及Etoposide (EP療法)的治療初期顯示了良好的反應，由於小細胞肺癌細胞惡性度高，加上投予二線藥物後的實質幫助不大，造成大部分患者的預後並不佳。有別於正常細胞經由粒線體氧化磷酸化產生能量，增生快速的癌細胞則偏好經由糖解作用進行乳酸發酵因應其能量需求，針對此重塑能量代謝途徑的特徵恰可做為治療癌症的重要標的。2-Deoxyglucose (2-DG)則是一種葡萄糖類似物，能與葡萄糖競爭進而阻斷糖解作用的進行，使癌細胞因無法獲得足夠能量而走向死亡。因此，本研究欲測試糖解作用抑制劑2-DG是否能加強臨床化療藥物Cisplatin合併Etoposide對小細胞肺癌細胞株H146和H209之抗癌效果，並接續探討三重藥物組合對細胞週期及細胞內訊號傳遞路徑分子的影響。研究結果顯示在小細胞肺癌細胞株H146和H209中，2-DG與Cisplatin及Etoposide的三藥合併比任一藥物單獨使用更顯著地抑制癌細胞生長，並且誘導細胞進行細胞凋亡。經由細胞週期的分析，三藥合併造成細胞週期阻滯在G2/M時期並同時促進細胞核內DNA的片段化，伴隨細胞在Sub-G1期的累積量增加。而在訊號傳遞途徑的分析中，三藥合併透過減少ERK以及S6蛋白之磷酸化表現藉以抑制MAPK/ERK和mTOR兩訊號傳遞路徑下游的活化。綜合以上實驗結果，在相對低的濃度下，2-DG與現階段臨床抗癌藥物Cisplatin合併Etoposide的三重藥物組合對細胞生長具有加成的抑制效果，並增強對細胞的毒殺作用以提升小細胞肺癌細胞株對藥物之敏感性。因此，本研究認為此合併療法在未來治療小細胞肺癌的策略上是相當具有潛力的。

關鍵字

小細胞肺癌 ； 合併療法 ； 糖解作用抑制劑

並列摘要

Small cell lung cancer (SCLC) accounts for about 10-15% of all diagnosed lung cancers, which is also the most aggressive form of lung cancer characterized by rapid progression, early metastasis, and the acquisition of drug resistance. In spite of the initially high response rate to the first-line chemotherapy with the combination of cisplatin and etoposide, unfortunately, most patients show poor clinical outcomes due to recurrent disease with drug resistance and limited benefits of further treatment after receiving second-line therapy. In contrast to normal cells primarily relying on mitochondrial oxidative phosphorylation, cancer cells exhibit the preference of using glycolysis followed by lactic acid fermentation in energy production to support their rapid proliferation. This hallmark of reprogramming energy metabolism in cancer cells thus has been used to develop the new targeted therapy. 2-Deoxyglucose (2-DG) is a glucose analog which is characterized as a glycolytic inhibitor that causes intracellular ATP depletion, subsequently suppresses cell growth and induces cell death. Therefore, the purpose of this study is to examine whether 2-DG potentiate the anticancer effects of cisplatin/etoposide in SCLC cell lines, then research on the cell cycle distribution and proliferation-related proteins in signaling transduction. Our results first demonstrated enhanced inhibitory effects on cell proliferation and further induced apoptosis by the triple combination compared with either 2-DG or cisplatin/etoposide alone. With the analysis of cell cycle, 2-DG combined with cisplatin/etoposide resulted in a G2/M-phase arrested cell population and further apoptotic DNA fragmentation along with an increased proportion of cells in Sub-G1. Moreover, we found that the combined treatment caused a reduction in ERK and S6 phosphorylation suggesting it could inhibit the downstream effectors of MAPK/ERK and mTOR signaling pathway. In summary, these results confirm that the triple combination with the low concentration of 2-DG and chemotherapeutic agents cisplatin/etoposide enhanced apoptosis-induced anticancer effects and cytotoxic activity in SCLC cell lines. Accordingly, we suggest that this combination regimen as a potential strategy for SCLC treatment in the future.

並列關鍵字

small cell lung cancer ； combination therapy ； glycolysis inhibitor

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