Department of Geriatrics, Shanghai Changning Center Hospital, Shanghai 200336, China.
Department of Geriatrics, Shanghai Changning Center Hospital, Shanghai 200336, China.
Biochem Biophys Res Commun. 2014 Sep 26;452(3):768-74. doi: 10.1016/j.bbrc.2014.08.147. Epub 2014 Sep 6.
Lung cancer is a major cause of cancer-related mortality in the United States and around the world. Due to the pre-existing or acquired chemo-resistance, the current standard chemotherapy regimens only show moderate activity against lung cancer. In the current study, we explored the potential anti-lung cancer activity of cinobufotalin in vivo and in vitro, and studied the underlying mechanisms. We demonstrated that cinobufotalin displayed considerable cytotoxicity against lung cancer cells (A549, H460 and HTB-58 lines) without inducing significant cell apoptosis. Our data suggest that mitochondrial protein cyclophilin D (Cyp-D)-dependent mitochondrial permeability transition pore (mPTP) opening mediates cinobufotalin-induced non-apoptotic death of lung cancer cells. The Cyp-D inhibitor cyclosporine A (CsA), the mPTP blocker sanglifehrin A (SfA), and Cyp-D shRNA-silencing significantly inhibited cinobufotalin-induced mitochondrial membrane potential (MMP) reduction and A549 cell death (but not apoptosis). Using a mice xenograft model, we found that cinobufotalin inhibited A549 lung cancer cell growth in vivo. Thus, cinobufotalin mainly induces Cyp-D-dependent non-apoptotic death in cultured lung cancer cells. The results of this study suggest that cinobufotalin might be further investigated as a novel anti-lung cancer agent.
肺癌是美国和全球癌症相关死亡的主要原因。由于存在预先存在的或获得性的化疗耐药性，目前的标准化疗方案对肺癌仅显示出中等活性。在本研究中，我们在体内和体外探索了华蟾素对肺癌的潜在抗癌活性，并研究了其潜在机制。我们证明华蟾素对肺癌细胞（A549、H460 和 HTB-58 系）具有相当的细胞毒性，而不会诱导明显的细胞凋亡。我们的数据表明，线粒体蛋白亲环素 D（Cyp-D）依赖性线粒体通透性转换孔（mPTP）开放介导华蟾素诱导的非凋亡性肺癌细胞死亡。亲环素 D 抑制剂环孢菌素 A（CsA）、mPTP 阻断剂桑福拉嗪 A（SfA）和 Cyp-D shRNA 沉默显著抑制华蟾素诱导的线粒体膜电位（MMP）降低和 A549 细胞死亡（而非凋亡）。使用小鼠异种移植模型，我们发现华蟾素在体内抑制 A549 肺癌细胞生长。因此，华蟾素主要在培养的肺癌细胞中诱导 Cyp-D 依赖性非凋亡性死亡。本研究结果表明，华蟾素可能作为一种新型的抗癌药物进一步研究。
