mTOR訊息傳遞路徑抑制劑於小細胞肺癌的抗癌效果之研究

Abstract

肺癌位居於台灣十大癌症死因之首，其中小細胞肺癌(small cell lung cancer)占所有肺癌中比例約百分之十五，且與非小細胞肺癌相比具有高度侵襲性、迅速增長、早期傳播和抗藥性等特性。迄今為止，化學治療仍然是小細胞肺癌患者最主要的臨床治療方法。因此，在臨床上急需發展出嶄新的治療策略。在這項研究中，我們將研究mTOR訊息傳遞路徑抑制劑對於小細胞肺癌的抗癌效果，本研究選用二甲雙胍(Metformin, Met)作為mTOR訊息傳遞路徑抑制劑，Metformin是一種雙胍類藥物，為現在經過美國FDA核淮用於治療第二型糖尿病患者(T2D)的第一線用藥，其主要作用是透過抑制mTOR訊息傳遞路徑下游蛋白S6及4E-BP1和MAPK訊息傳遞路徑下游蛋白Erk 1/2的磷酸化。在實驗結果顯示，Metformin可以增強對小細胞肺癌的細胞毒殺性及促進癌細胞走向凋亡。然後，在研究中也發現Metformin與現階段臨床化療藥物配合使用後，能增強它們在小細胞肺癌的細胞毒性和誘導細胞凋亡的效果。總結以上之結果，本研究建議Metformin有潛力成為單獨或合併使用作為小細胞肺癌的標靶治療藥物。

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. In this study, we examined the anti-proliferative effects of metformin on SCLC. The metformin (Met) is a derivative of Biguanides and is now the most widely prescribed oral anti-diabetic agent worldwide, which mainly acts through inactivation of the mTOR pathway and suppression its downstream family proteins in many different types of cancers. Our results showed that the metformin enhanced cell toxicity with time- and concentration-dependent induced cell apoptosis in the H209 and H146 SCLC cell lines. Furthermore, the metformin inhibited cell proliferation through causing cell cycle arrested in G0/G1 and G2/M phase. AnnexinV/propidium iodide staining by flow cytometric exhibited nuclear feature of apoptosis with the increasing annexin V positive apoptotic cell proportion in a dose-dependent manner. In the analysis of the signaling transduction pathways, the mTOR and Erk 1/2 signaling proteins were affected by metformin treatments in SCLC cells. In addition, co-treatment with metformin does effectively enhance cisplatin, etoposide, topotecan or 5-fluorouracil mediated cell toxicity and can induce apoptosis. In summary, our results suggest that metformin may be a potential target therapeutic agent in the treatment of SCLC.