A novel parthenin analog exhibits anti-cancer activity: Activation of apoptotic signaling events through robust NO formation in human leukemia HL-60 cells
A novel parthenin analog exhibits anti-cancer activity: Activation of apoptotic signaling events through robust NO formation in human leukemia HL-60 cells
复制标题
DOI：
10.1016/j.cbi.2011.06.006
复制
发表时间：
2011-09-30
影响因子：
5.1
通讯作者：
Singh, Jaswant
中科院分区：
文献类型：
--
作者：
Kumar, Ajay;Malik, Fayaz;Singh, Jaswant
本研究描述了P19的抗癌活性，P19是parthenin的类似物。P19诱导HL-60细胞凋亡，抑制细胞增殖，48 h IC 50为3.5 μ M。在10 mg/kg剂量下，它使L1210白血病小鼠的中位生存时间增加一倍，在25 mg/kg剂量下，它抑制埃利希腹水肿瘤生长60%。对P19诱导HL-60细胞凋亡机制的研究表明，N-乙酰-L-半胱氨酸（NAC）和s-甲基异硫脲（sMIT）可通过抑制一氧化氮（NO）的生成逆转导致细胞凋亡的分子事件。它选择性地在细胞中产生大量NO，同时淬灭基础ROS水平，同时升高GSH。P19破坏线粒体完整性，导致细胞色素c释放和半胱天冬酶-9活化。P19还通过选择性地升高DR 4和DR 5的表达而引起caspase-8活化。所有这些事件导致半胱天冬酶-3活化，导致PARP-1裂解和DNA片段化。然而，通过siRNA敲低AIF也基本上抑制了凋亡，因此也表明不依赖于半胱天冬酶的凋亡。此外，与增强的iNOS表达相反，其转录因子NF-κ B（p65）被裂解，同时胞质I κ B-α增加。此外，P19有效地抑制促存活蛋白pSTAT 3和存活素。P19的多模式促凋亡活性提高了其作为有希望的抗癌治疗剂的潜在有用性。(C)2011爱思唯尔爱尔兰有限公司保留所有权利。
This study describes the anti-cancer activity of P19, an analog of parthenin. P19 induced apoptosis in HL-60 cells and inhibited cell proliferation with 48 h IC50 of 3.5 mu M. At 10 mg/kg dose, it doubled the median survival time of L1210 leukemic mice and at 25 mg/kg it inhibited Ehrlich ascites tumor growth by 60%. Investigation of the mechanism of P19 induced apoptosis in HL-60 cells revealed that N-acetyl-L-cysteine (NAC) and s-methylisothiourea (sMIT) could reverse several molecular events that lead to cell death by inhibiting nitric oxide (NO) formation. It selectively produced massive NO in cells while quenching the basal ROS levels with concurrent elevation of GSH. P19 disrupted mitochondrial integrity leading to cytochrome c release and caspase-9 activation. P19 also caused caspase-8 activation by selectively elevating the expression of DR4 and DR5. All these events lead to the activation of caspase-3 leading to PARP-1 cleavage and DNA fragmentation. However, knocking down of AIF by siRNA also suppressed the apoptosis substantially thus indicating caspase independent apoptosis, too. Further, contrary to enhanced iNOS expression, its transcription factor, NF-kappa B (p65) was cleaved with a simultaneous increase in cytosolic I kappa B-alpha. In addition, P19 potently inhibited pro-survival proteins pSTAT3 and survivin. The multi-modal pro-apoptotic activity of P19 raises its potential usefulness as a promising anti-cancer therapeutic. (C) 2011 Elsevier Ireland Ltd. All rights reserved.