Ahmad Aamir, Banerjee Sanjeev, Wang Zhiwei, Kong Dejuan, Sarkar Fazlul H
Department of Pathology, Barbara Ann Karmanos Cancer Center and Wayne State University School of Medicine, Detroit, Michigan 48201, USA.
J Cell Biochem. 2008 Dec 15;105(6):1461-71. doi: 10.1002/jcb.21966.
Breast cancer remains the major cause of cancer-related deaths in women world-wide. The heterogeneity of breast cancer has further complicated the progress of target-based therapies. Triple negative breast cancers, lacking estrogen receptor, progesterone receptor and the Her-2/neu (ErbB2), represent a highly aggressive breast cancer subtype, that are difficult to treat. Pleiotropic agents, such as those found in nature, can target receptor-positive as well as receptor-negative cancer cells, suggesting that such agents could have significant impact in breast cancer prevention and/or therapy. Plumbagin (5-hydroxy-2-methyl-1, 4-naphthoquinone) is one such agent which has anti-tumor activity against several cancers. However, its mechanism of action against breast cancer is not clearly understood. We hypothesized that plumbagin may act as an effective agent against breast cancer especially triple negative breast cancer. We tested our hypothesis using ER-positive MCF-7 and ER-negative MDA-MB-231 (triple negative) breast cancer cells, and we found that plumbagin significantly inhibits the growth of breast cancer cells with no effect on normal breast epithelial cells. We also found that plumbagin induces apoptosis with concomitant inactivation of Bcl-2 and the DNA binding activity of NF-kappaB. Bcl-2 over-expression resulted in attenuation of plumbagin-induced effects, suggesting that the inhibition of cell growth and induction of apoptosis by plumbagin is in part due to inactivation of NF-kappaB/Bcl-2 pathway. To our knowledge, this is the first report, showing mechanistic and cancer cell specific apoptosis-inducing effects of plumbagin in breast cancer cells, suggesting the potential role of plumbagin in the prevention and/or treatment of breast cancer.
乳腺癌仍然是全球女性癌症相关死亡的主要原因。乳腺癌的异质性使基于靶点的治疗进展更加复杂。三阴性乳腺癌缺乏雌激素受体、孕激素受体和Her-2/neu（ErbB2），是一种极具侵袭性的乳腺癌亚型，难以治疗。多效性药物，如天然存在的那些药物，可以靶向受体阳性和受体阴性癌细胞，这表明此类药物可能对乳腺癌的预防和/或治疗有重大影响。白花丹醌（5-羟基-2-甲基-1,4-萘醌）就是这样一种对多种癌症具有抗肿瘤活性的药物。然而，其抗乳腺癌的作用机制尚不清楚。我们假设白花丹醌可能是一种有效的抗乳腺癌药物，尤其是对三阴性乳腺癌。我们使用雌激素受体阳性的MCF-7和雌激素受体阴性的MDA-MB-231（三阴性）乳腺癌细胞来验证我们的假设，发现白花丹醌能显著抑制乳腺癌细胞的生长，而对正常乳腺上皮细胞没有影响。我们还发现白花丹醌诱导细胞凋亡，同时使Bcl-2失活并降低NF-κB的DNA结合活性。Bcl-2过表达导致白花丹醌诱导的效应减弱，这表明白花丹醌对细胞生长的抑制和对细胞凋亡的诱导部分是由于NF-κB/Bcl-2信号通路的失活。据我们所知，这是第一份报告，展示了白花丹醌在乳腺癌细胞中的作用机制和癌细胞特异性凋亡诱导作用，提示白花丹醌在乳腺癌预防和/或治疗中的潜在作用。
