Research Center, Tangdu Hospital, Fourth Military Medical University, Xinsi Road, 710038, Xi'an, Shaanxi Province, People's Republic of China.
Med Oncol. 2011 Dec;28(4):1225-54. doi: 10.1007/s12032-010-9552-x. Epub 2010 May 11.
Arsenic trioxide (As2O3), a component of traditional Chinese medicine, has been used successfully for the treatment of acute promyelocytic leukemia (APL), and As2O3 is of potential therapeutic value for the treatment of other promyelocytic malignancies and some solid tumors including breast cancer. However, the precise molecular mechanisms through which As2O3 induces cell cycle arrest and apoptosis in solid tumors have not been clearly understood. The goal of our study is to gain insight into the general biological processes and molecular functions that are altered by As2O3 treatment in MCF-7 breast cancer cells and to identify the key signaling processes that are involved in the regulation of these physiological effects. In the present study, MCF-7 cells were treated with 5 μM As2O3, and the differential gene expression was then analyzed by DNA microarray. The results showed that As2O3 treatment changed the expression level of several genes that involved in cell cycle regulation, signal transduction, and apoptosis. Notably, As2O3 treatment increased the mRNA and protein levels of the cell cycle inhibitory proteins, p21 and p27. Interestingly, knocking down p21 or p27 individually did not alter As2O3-induced apoptosis and cell cycle arrest; however, the simultaneous down-regulation of both p21 and p27 resulted in attenuating of G1, G2/M arrest and reduction in apoptosis, thus indicating that p21 and p27 as the primary molecular targets of As2O3 against breast cancer. Overall, our results provide new insights into As2O3-related signaling activities, which may facilitate the development of As2O3-based anticancer strategies and/or combination therapies against solid tumors.
三氧化二砷（As2O3）是一种传统中药的成分，已成功用于治疗急性早幼粒细胞白血病（APL），并且 As2O3 对于治疗其他早幼粒细胞恶性肿瘤和一些实体瘤，包括乳腺癌，具有潜在的治疗价值。然而，As2O3 在实体瘤中诱导细胞周期停滞和凋亡的确切分子机制尚未清楚。我们的研究目的是深入了解 As2O3 处理在 MCF-7 乳腺癌细胞中改变的一般生物学过程和分子功能，并确定涉及这些生理效应调节的关键信号过程。在本研究中，用 5μM As2O3 处理 MCF-7 细胞，然后通过 DNA 微阵列分析差异基因表达。结果表明，As2O3 处理改变了几个涉及细胞周期调节、信号转导和凋亡的基因的表达水平。值得注意的是，As2O3 处理增加了细胞周期抑制蛋白 p21 和 p27 的 mRNA 和蛋白水平。有趣的是，单独敲低 p21 或 p27 并不改变 As2O3 诱导的细胞凋亡和细胞周期停滞；然而，同时下调 p21 和 p27 导致 G1、G2/M 期阻滞和凋亡减少，表明 p21 和 p27 是 As2O3 针对乳腺癌的主要分子靶标。总的来说，我们的结果为 As2O3 相关信号活性提供了新的见解，这可能有助于开发基于 As2O3 的抗癌策略和/或针对实体瘤的联合治疗。
