Abstract：
Lung cancer is the leading cause of cancer deaths, where the metastasis often causes chemodrug resistance and leads to recurrence after treatment. Desmethylclomipramine (DCMI), a bioactive metabolite of clomipramine, shows the therapeutic efficacy with antidepressive agency as well as potential cytostatic effects on lung cancer cells. Here, we demonstrated that DCMI effectively caused transforming growth factor (TGF)-β1-mediated mesenchymal type of A549 cells to undergo mitochondrial death via myeloid cell leukemia-1 (Mcl-1) suppression and activation of truncated Bid (tBid). TGF-β1 induced epithelial mesenchymal transition in A549 cells with the increase of fibronectin and decrease of E-cadherin, the activation of Akt/glycogen synthase kinase-3β (GSK-β)/Mcl-1 axis, and the hypo-responsiveness to cisplatin. DCMI initiated a dose-dependent cytotoxicity on TGF-β1-mediated mesenchymal type of A549 cells through inactivating Akt/GSK-β/Mcl-1 axis, in which mitochondria instability and caspase-9/3 activation also occurred concurrently. Pharmacological inhibition of caspase-8 and cathepsin B partly reversed tBid expression and mitochondrial damage to further attenuate DCMI-mediated cytotoxicity. Additionally, DCMI presented partial therapeutic effects in treating mesenchymal type of A549 tumor bearing nude mice through an acceleration of cancer cell death. Taken together, DCMI exerts antitumor effects via initiating the mechanisms of Akt/GSK-β/Mcl-1 inactivation and cathepsin B/caspase-8-regulated mitochondrial death, which suggests its potential role in mesenchymal type of cancer cell therapy.
摘要：
肺癌是导致癌症死亡的主要原因，转移通常会导致化疗耐药，并导致治疗后复发。去甲基氯米帕明（DCMI），氯米帕明的生物活性代谢产物,显示了抗抑郁药的疗效以及对肺癌细胞的潜在细胞抑制作用。这里,我们证明,DCMI通过髓样细胞白血病-1(Mcl-1)抑制和截短Bid(tBid)激活,有效地导致转化生长因子(TGF)-β1介导的间充质型A549细胞发生线粒体死亡.TGF-β1诱导A549细胞上皮间质转化,与纤维连接蛋白的增加和E-cadherin的减少有关,Akt/糖原合成酶激酶-3β（GSK-β）/Mcl-1轴的激活，和对顺铂的低反应性。DCMI通过灭活Akt/GSK-β/Mcl-1轴对TGF-β1介导的间充质型A549细胞产生剂量依赖性细胞毒性,其中线粒体不稳定和caspase-9/3激活也同时发生。caspase-8和组织蛋白酶B的药理学抑制部分逆转了tBid表达和线粒体损伤，进一步减弱了DCMI介导的细胞毒性。此外,DCMI通过加速癌细胞死亡在治疗间充质型A549荷瘤裸鼠中表现出部分治疗作用。一起来看,DCMI通过启动Akt/GSK-β/Mcl-1失活和组织蛋白酶B/caspase-8调节线粒体死亡的机制发挥抗肿瘤作用。这表明它在间质型癌细胞治疗中的潜在作用。
