Wong Fang Cheng, Woo Chern Chiuh, Hsu Annie, Tan Benny Kwong Huat
Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.
PLoS One. 2013 Oct 24;8(10):e78021. doi: 10.1371/journal.pone.0078021. eCollection 2013.
Breast cancer is currently the leading cause of cancer-related deaths among women globally. Notably, medicinal plant extracts may be a potential source for treatments of breast cancer. Vernonia amygdalina (VA) is a woody shrub reported to have not only diverse therapeutic effects but also anti-cancer properties. However, current research about the mechanisms of the anti-cancer potential of VA has been limited. This study aimed to investigate the mechanisms of action of VA that underlie its anti-cancer effects in human breast cancer cell lines (MCF-7 and MDA-MB-231 cells). Results from MTT assay revealed that VA inhibits the proliferation of MCF-7 and MDA-MB-231, in a time- and dose-dependent manner. The underlying mechanism of this growth inhibition involved the stimulation of cell-type specific G1/S phase cell cycle arrest in only MCF-7 cells, and not in MDA-MB-231 cells. While the growth arrest was associated with increased levels of p53 and p21, and a concomitant decrease in the levels of cyclin D1 and cyclin E, it was shown that VA causes cell cycle arrest through a p53-independent pathway as tested by the wild type p53 inhibitor, pifithrin-α. Furthermore, this study revealed that VA induces apoptosis in the two cell lines, as indicated by the increase in Annexin V-positive cells and sub-G1 population, and that this VA-induced apoptosis occurred through both extrinsic and intrinsic apoptotic pathways. The apoptosis in MCF-7 cells was also likely to be caspase-dependent and not p53 transcriptional-dependent. Given that approximately 70% of diagnosed breast cancers express ER-α, a crucial finding was that VA inhibits the expression of ER-α and its downstream player, Akt, highlighting the potential clinical significance of VA. Moreover, VA exhibits synergism when combined with doxorubicin, suggesting that it can complement current chemotherapy. Overall, this study demonstrates the potential applications of VA as an anti-cancer drug for breast cancer treatment.
乳腺癌是目前全球女性癌症相关死亡的主要原因。值得注意的是，药用植物提取物可能是治疗乳腺癌的潜在来源。扁桃斑鸠菊（VA）是一种木本灌木，据报道不仅具有多种治疗作用，还具有抗癌特性。然而，目前关于VA抗癌潜力机制的研究有限。本研究旨在探讨VA在人乳腺癌细胞系（MCF-7和MDA-MB-231细胞）中发挥抗癌作用的作用机制。MTT分析结果显示，VA以时间和剂量依赖性方式抑制MCF-7和MDA-MB-231的增殖。这种生长抑制的潜在机制仅涉及在MCF-7细胞中刺激细胞类型特异性的G1/S期细胞周期停滞，而在MDA-MB-231细胞中则没有。虽然生长停滞与p53和p21水平的增加以及细胞周期蛋白D1和细胞周期蛋白E水平的相应降低有关，但如通过野生型p53抑制剂pifithrin-α测试所示，VA通过p53非依赖性途径导致细胞周期停滞。此外，本研究表明，VA诱导这两种细胞系凋亡，膜联蛋白V阳性细胞和亚G1期群体增加表明了这一点，并且这种VA诱导的凋亡通过外源性和内源性凋亡途径发生。MCF-7细胞中的凋亡也可能是半胱天冬酶依赖性的，而不是p53转录依赖性的。鉴于大约70%的确诊乳腺癌表达雌激素受体α（ER-α），一个关键发现是VA抑制ER-α及其下游因子Akt的表达，突出了VA的潜在临床意义。此外，VA与多柔比星联合使用时表现出协同作用，表明它可以补充当前的化疗。总体而言，本研究证明了VA作为乳腺癌治疗抗癌药物的潜在应用。
