Melanoma is the leading cause of skin cancer deaths, and the poor prognosis of metastatic melanoma has made needs for a novel pharmacological treatment or efficient intervention. Carnosol, a major polyphenolic compound from Rosmarinus officinalis, has a wide range of biological activities including anti-cancer effect. However, the underlying molecular mechanisms of its anti-cancer effect remain poorly understood in malignant human melanoma cells. In the present study, we investigate the apoptotic effect and the underlying anti-cancer mechanisms of carnosol. Our results revealed that carnosol strongly induced apoptosis against human melanoma G361 cells in a dose- and time-dependent manner, and caused dramatical elevation in cellular reactive oxygen species (ROS) level during apoptosis. In mechanistic studies, carnosol treatment decreased protein level of anti-apoptotic B‑cell lymphoma 2 (Bcl-2) and B cell lymphoma-extra large (Bcl-xL), however, increased level of pro-apoptotic Bcl-2-associated X protein (Bax) protein. Moreover, carnosol escalated cellular level of p53, which was accompanied by a decline of mouse double minute 2 homolog (MDM2) level. Also, carnosol inhibited activation of Src and signal transducer and activator of transcription 3 (STAT3), therefore down-regulated STAT3-dependent gene expression, such as D-series cyclin and survivin. These changes by carnosol were attenuated by pre-treatment of N-acetyl cysteine, and abolished progression of carnosol-induced apoptosis. In conclusion, carnosol induced apoptosis in human melanoma G361 cells through ROS generation and inhibition of STAT3-mediated pathway. Our results provide molecular bases of carnosol-induced apoptosis, and suggest a novel candidate for human melanoma treatment.

中文翻译：

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鼠尾草酚通过ROS依赖性灭活人类黑素瘤G361细胞中的STAT3诱导凋亡性细胞死亡

黑色素瘤是导致皮肤癌死亡的主要原因，而转移性黑色素瘤的不良预后使得需要新的药物治疗或有效的干预措施。鼠尾草酚是迷迭香的主要多酚化合物，具有多种生物活性，包括抗癌作用。然而，其抗癌作用的潜在分子机制在恶性人黑素瘤细胞中仍知之甚少。在本研究中，我们研究了鼠尾草酚的凋亡作用及其潜在的抗癌机制。我们的结果表明，鼠尾草酚以剂量和时间依赖性方式强烈诱导人黑素瘤G361细胞凋亡，并在凋亡过程中引起细胞活性氧（ROS）水平急剧升高。在力学研究中，鼠尾草酚治疗可降低抗凋亡B细胞淋巴瘤2（Bcl-2）和超大型B细胞淋巴瘤（Bcl-xL）的蛋白水平，但是，促凋亡Bcl-2相关X蛋白（Bax）的水平升高蛋白。此外，鼠尾草酚升高了p53的细胞水平，并伴随着小鼠双分2同源物（MDM2）水平的降低。同样，鼠尾草酚抑制Src的激活以及信号转导和转录激活因子3（STAT3）的激活，因此下调了STAT3依赖性基因表达，例如D系列细胞周期蛋白和survivin。卡诺索尔的这些变化被N-乙酰基半胱氨酸的预处理所减弱，并消除了卡诺索尔诱导的细胞凋亡的进程。总之，鼠尾草酚通过ROS产生和STAT3介导的途径的抑制诱导人黑素瘤G361细胞凋亡。