對於診斷為第三期非小細胞肺癌無法手術切除的病人，標準治療為鉑金屬為根基，使用兩種藥物處方同步的化學與放射治療，許多醫師期待能尋找出更有效且更低副作用的單一藥物，處方在同步的化學與放射治療。我們審閱68位第三期非小細胞肺癌的病人之病歷，42位接受溫諾平同步的化學與放射治療，26位只接受放射治療，結果發現同步的化學與放射治療組反應率為66.7%，優於放射治療組30.8% ( P < 0.001)。這個研究的主要目標是探討溫諾平的細胞毒殺機制，與此藥物如何在同步的化學與放射治療中造成加乘反應。
首先我們要探究溫諾平導致肺癌細胞生長抑制與凋亡的機制，觀察發現溫諾平使得細胞分裂時停在前中期，接著使得粒線體模電位消失、Mcl-1減少與caspase相關的細胞凋亡，JNK的持續活化才能使溫諾平的細胞凋亡發生，但不會影響細胞週期，除此之外溫諾平也會使得glutathione與ROS間失去平衡，而抑制ROS會使得接下來的JNK的活化、Mcl-1減少、粒線體模電位消失與細胞凋亡均不會發生，溫諾平也會促發JNK調控的DNA傷害在前中期，結論是ROS扮演舉足輕重的角色，在溫諾平誘發JNK的活化、Mcl-1減少、DNA傷害、粒線體功能失常的細胞凋亡，但和細胞週期變化無關。
接著我們研究glucosylceramide synthase抑制作用在溫諾平同步化學與放射治療上的角色，同步化學與放射治療會增加細胞週期停滯與凋亡，JNK的活化細胞也會增加凋亡，但和細胞週期變化無關，這個治療也會增加ceramide累積，卻減少glucosylceramide生成，產生細胞毒殺的效應；利用藥物來抑制glucosylceramide synthase，會增強溫諾平與溫諾平同步化學與放射治療誘發的細胞凋亡，這樣的機制主要是經由JNK來調控。所以抑制glucosylceramide synthase，會促使溫諾平對於放射治療的加強反應，經由JNK活化導致肺癌細胞凋亡。

The standard treatment regimen for patients who are diagnosed with unsectable locally advanced stage III non-small cell lung cancer (NSCLC) is platinum-based doublet regimen concurrent chemoradiotherapy (CCRT). Many doctors have expressed an interest in identifying more active and better tolerated single agent for the treatment. We reviewed the records of 68 patients with stage III NSCLC: 42 patients received VNR-based CCRT, and 26 were treated with radiation alone. There was response rate of 66.7% in patients with CCRT, which was better than the patients with radiation alone (30.8%; P < 0.001). This study investigated the molecular cytotoxic mechanism of VNR and synergistic effects of VNR-based CCRT.
First, we identify the molecular mechanisms underlying growth inhibition as well as apoptosis in VNR-treated lung adenocarcinoma cells. Treatment with VNR caused mitotic prometaphase arrest, accompanied by cell apoptosis. VNR sequentially induced mitochondrial transmembrane potential (MTP) loss and caspase-dependent apoptosis following myeloid cell leukemia (Mcl) 1 downregulation. Prolonged activation of c-Jun N-terminal kinase (JNK) was required for VNR-induced apoptosis but not cell cycle arrest. VNR caused glutathione/reactive oxygen species (ROS) imbalance, and inhibiting ROS prevented prolonged JNK activation, decreased Mcl-1 levels, MTP loss, and apoptosis. VNR induced aberrant JNK-regulated DNA damage in prometaphase. These results demonstrate an essential role of ROS in VNR-induced aberrant JNK-mediated Mcl-1 downregulation and DNA damage followed by mitochondrial dysfunction-related apoptosis but not mitotic arrest.
Second, human lung adenocarcinoma cells were used in this study to investigate the molecular effects of glucosylceramide synthase inhibition on VNR-based CCRT. CCRT caused an increase in cell cycle arrest at G2/M phase accompanied by apoptosis. Oxidative c-Jun N-terminal kinase (JNK) activation was involved in the increased apoptosis levels but not the cell cycle arrest. CCRT also induced an increase in ceramide accompanied by a decrease in glucosylceramide that was positively correlated with the cytotoxic effects. Pharmacologically inhibiting glucosylceramide synthase facilitated VNR- and CCRT-induced apoptosis by promoting the JNK pathway. Inhibiting glucosylceramide synthase facilitates the radiosensitizing effects of VNR by promoting JNK-mediated apoptosis in lung adenocarcinoma cells.

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