藉由Bortezomib抑制26S蛋白酶體合併化療藥物在小細胞肺癌的細胞毒殺效果之研究

Abstract

癌症是國人十大死因的第一名，其中肺癌更是名列前茅。最近幾年臺灣每年有將近6000人死於肺癌。近年來儘管醫學已有相當進展，但是肺癌的治療成果還是非常令人失望。肺癌約有10%至15%屬於小細胞肺癌(SCLC)。與非小細胞肺癌(NSCLC)相比小細胞肺癌(SCLC)之癌細胞很小，癌細胞增生很快，診斷時有一半以上的病患已發生轉移遠處器官，但是仍對化學治療有很高的敏感度，近半數的患者於化學治療後腫瘤會完全消失，雖然小細胞肺癌對於對化學治療及放射線治療的效果比較好，但是病患的存活率卻很低，接受治療的病人過半數可以得到緩解，卻也容易在短時間內復發轉移。抗細胞凋亡蛋白BCL-2，被發現在小細胞肺癌(SCLC)中大量表現，它是由NF-κB訊息傳遞路徑所調控，其與小細胞肺癌(SCLC)對於化學治療的化學抗藥性也有關係。根據以往的研究指出，使用Bortezomib於小細胞肺癌(SCLC)中，藉由抑制NF-κB訊息傳遞路徑，可以有效地降低抗細胞凋亡蛋白BCL-2的表現量以及避免造成化學抗藥性。Bortezomib是一種26S蛋白酶體抑制劑，在此次實驗中，我們利用Bortezomib結合其他種類的化學治療藥物Etoposide和Paclitaxel來增強對小細胞肺癌(SCLC)的治療效果。從實驗結果看來，結合標靶治療藥物與化學治療藥物，比單一種治療方式能更有效地影響癌細胞存活率，抑制NF-κB訊息傳遞路徑，減少抗細胞凋亡蛋白BCL-2的表現量以及能更有效地引起癌細胞進行細胞凋亡。

Small cell lung cancer (SCLC) accounts for approximately 10~15% of lung cancer. SCLC is more responsive to chemotherapy and radiation therapy than other cell types of lung cancer; however, a cure is difficult to achieve because SCLC has a greater tendency to be widely disseminated by the time of diagnosis. Although small cell lung cancer is sensitive to chemotherapy, the survival rate of patients, however, were exceedingly poor, because almost all of the patients were in a period of time, the majority of patients usually produce relapse within six months or a year. Over the last decade new drugs in small cell lung cancer, either first-line or second-line treatment, the results are not very well. It may be possible to solve the problem by Combining chemotherapy and targeted therapy. Overexpression of the anti-apoptotic protein BCL-2, a protein regulated by anti-apoptotic NF-κB pathway, is frequently observed in small cell lung cancer (SCLC) and is associated with chemoresistance. Treatment with brotezomib, a targeted therapy drug, can decrease BCL-2 level by suppressing anti-apoptotic NF-κB pathway has been reported in small cell lung cancer (SCLC).In this study, by decreasing BCL-2 level to avoid chemoresistance,we can combine brotezomib and SCLC chemotherapy drugs to enhance therapeutic ability. In addition, combining chemotherapy and targeted therapy affected cell viability and induced cell apoptosis which is more effective than single chemotherapy or targeted therapy.