印度草医学植物化学物质Withaferin A对乳腺癌化学预防的疾病亚型非依赖性生物标志物
Disease Subtype-Independent Biomarkers of Breast Cancer Chemoprevention by the Ayurvedic Medicine Phytochemical Withaferin A.
作者信息
Samanta Suman K, Sehrawat Anuradha, Kim Su-Hyeong, Hahm Eun-Ryeong, Shuai Yongli, Roy Ruchi, Pore Subrata K, Singh Krishna B, Christner Susan M, Beumer Jan H, Davidson Nancy E, Singh Shivendra V
机构信息
Department of Pharmacology and Chemical Biology.
Department of Biostatistics.
出版信息
J Natl Cancer Inst. 2016 Dec 31;109(6). doi: 10.1093/jnci/djw293. Print 2017 Jun.
BACKGROUND
A nontoxic chemopreventive intervention efficacious against different subtypes of breast cancer is still a clinically unmet need. The present study was undertaken to determine the efficacy of an Ayurvedic medicine phytochemical (Withaferin A, [WA]) for chemoprevention of breast cancer and to elucidate its mode of action.
METHODS
Chemopreventive efficacy of WA (4 and 8 mg/kg body weight) was determined using a rat model of breast cancer induced by N-methyl-N-nitrosourea (MNU; n = 14 for control group, n = 15 for 4 mg/kg group, and n = 18 for 8 mg/kg group). The mechanisms underlying breast cancer chemoprevention by WA were elucidated by immunoblotting, biochemical assays, immunohistochemistry, and cytokine profiling using plasma and tumors from the MNU-rat (n = 8-12 for control group, n = 7-11 for 4 mg/kg group, and n = 8-12 for 8 mg/kg group) and/or mouse mammary tumor virus-neu (MMTV-neu) models (n = 4-11 for control group and n = 4-21 for 4 mg/kg group). Inhibitory effect of WA on exit from mitosis and leptin-induced oncogenic signaling was determined using MCF-7 and/or MDA-MB-231 cells. All statistical tests were two-sided.
RESULTS
Incidence, multiplicity, and burden of breast cancer in rats were decreased by WA administration. For example, the tumor weight in the 8 mg/kg group was lower by about 68% compared with controls (8 mg/kg vs control, mean = 2.76 vs 8.59, difference = -5.83, 95% confidence interval of difference = -9.89 to -1.76, P = .004). Mitotic arrest and apoptosis induction were some common determinants of breast cancer chemoprevention by WA in the MNU-rat and MMTV-neu models. Cytokine profiling showed suppression of plasma leptin levels by WA in rats. WA inhibited leptin-induced oncogenic signaling in cultured breast cancer cells.
CONCLUSIONS
WA is a promising chemopreventative phytochemical with the ability to inhibit at least two different subtypes of breast cancer.
背景
一种对不同亚型乳腺癌有效的无毒化学预防干预措施仍是临床上未满足的需求。本研究旨在确定一种阿育吠陀药物植物化学物质（Withaferin A，[WA]）对乳腺癌化学预防的效果，并阐明其作用方式。
方法
使用N-甲基-N-亚硝基脲（MNU）诱导的大鼠乳腺癌模型（对照组n = 14，4 mg/kg组n = 15，8 mg/kg组n = 18）确定WA（4和8 mg/kg体重）的化学预防效果。通过免疫印迹、生化分析、免疫组织化学以及使用MNU大鼠（对照组n = 8 - 12，4 mg/kg组n = 7 - 11，8 mg/kg组n = 8 - 12）和/或小鼠乳腺肿瘤病毒-neu（MMTV-neu）模型（对照组n = 4 - 11，4 mg/kg组n = 4 - 21）的血浆和肿瘤进行细胞因子分析，阐明WA预防乳腺癌的潜在机制。使用MCF-7和/或MDA-MB-231细胞确定WA对有丝分裂退出和瘦素诱导的致癌信号传导的抑制作用。所有统计检验均为双侧检验。
结果
给予WA可降低大鼠乳腺癌的发病率、多发性和负担。例如，8 mg/kg组的肿瘤重量比对照组低约68%（8 mg/kg vs对照组，平均值 = 2.76 vs 8.59，差异 = -5.83，差异的95%置信区间 = -9.89至 -1.76，P = 0.004）。有丝分裂停滞和凋亡诱导是WA在MNU大鼠和MMTV-neu模型中预防乳腺癌的一些常见决定因素。细胞因子分析显示WA可抑制大鼠血浆瘦素水平。WA在培养的乳腺癌细胞中抑制瘦素诱导的致癌信号传导。
结论
WA是一种有前景的化学预防植物化学物质，能够抑制至少两种不同亚型的乳腺癌。
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