Chaetocin induces apoptosis in human melanoma cells through the generation of reactive oxygen species and the intrinsic mitochondrial pathway, and exerts its anti-tumor activity in vivo.
Chaetocin induces apoptosis in human melanoma cells through the generation of reactive oxygen species and the intrinsic mitochondrial pathway, and exerts its anti-tumor activity in vivo.
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DOI：
10.1371/journal.pone.0175950
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发表时间：
2017
期刊：
影响因子：
3.7
通讯作者：
Xu L
中科院分区：
文献类型：
--
作者：
Han X;Han Y;Zheng Y;Sun Q;Ma T;Zhang J;Xu L
毛壳素是由毛壳属真菌产生的一种小分子天然产物，对多种肿瘤细胞具有较强的抗增殖药理活性。然而，毛壳素对抗黑色素瘤药理作用的影响尚未研究。因此，在本研究中，我们探讨了毛壳素对人黑色素瘤Sk-Mel-28和A375细胞增殖和裸鼠移植瘤生长的影响。结果表明，毛壳素处理显着抑制细胞增殖和诱导凋亡的Sk-Mel-28和A375细胞在剂量和时间依赖性的方式。此外，毛壳素治疗导致细胞活性氧（ROS）的水平增加，和预孵育的细胞与N-乙酰半胱氨酸（NAC）显着废除毛壳素诱导的黑色素瘤细胞凋亡。毛壳素处理后，线粒体膜电位和细胞色素c的释放显着降低。此外，毛壳素处理显著上调了黑色素瘤细胞中Bax、切割的caspase-9/-3的蛋白水平，同时下调了Bcl-2、caspase-9/-3的蛋白水平，并激活了caspase-9/-3的活性。体内实验结果表明，毛壳素能显著抑制裸鼠移植瘤的生长，这与肿瘤细胞凋亡诱导、增殖细胞核抗原（PCNA）表达水平降低和半胱氨酸蛋白酶9/-3的激活密切相关。这些是第一个数据表明，毛壳素通过ROS的产生和内在的线粒体途径对人黑色素瘤细胞发挥促凋亡活性。因此，毛壳素可能是黑色素瘤化疗的有效候选物。
Chaetocin is a small-molecule natural product produced by Chaetomium species fungi, and it has a potent anti-proliferative pharmacological activity on various cancer cells. However, the effect of chaetocin on anti-melanoma pharmacological role has not been investigated. Therefore, in this study, we explored the effect of chaetocin on cell proliferation in the human melanoma Sk-Mel-28 and A375 cells and the growth of tumor xenografts in nude mice. The results indicated that chaetocin treatment significantly suppressed cell proliferation and induced apoptosis in the Sk-Mel-28 and A375 cells in a dose- and time-dependent manner. Furthermore, chaetocin treatment resulted in an increased level of cellular reactive oxygen species (ROS), and pre-incubation of cells with N-acetylcysteine (NAC) significantly abrogated chaetocin-induced apoptosis in the melanoma cells. A significant reduction of mitochondrial membrane potential and the release of cytochrome c were observed after chaetocin treatment. Additionally, chaetocin treatment significantly up-regulated the protein levels of Bax, cleaved caspase-9/-3, simultaneously down-regulated the protein levels of Bcl-2, procaspase-9/-3, and activated caspase-9/-3 activity in the melanoma cells. The in vivo data demonstrated that chaetocin treatment significantly inhibited the growth of melanoma tumor xenografts in nude mice, which was closely associated with apoptosis induction, a reduced level of PCNA (proliferating cell nuclear antigen) expression, and activation of capase-9/-3 in tumor xenografts. These are the first data to demonstrate that chaetocin exerts a proapoptotic activity on human melanoma cells through ROS generation and the intrinsic mitochondrial pathway. Therefore, chaetocin might represent an effective candidate for melanoma chemotherapy.