A novel microtubule-modulating agent induces mitochondrially driven caspase-dependent apoptosis via mitotic checkpoint activation in human prostate cancer cells.
A novel microtubule-modulating agent induces mitochondrially driven caspase-dependent apoptosis via mitotic checkpoint activation in human prostate cancer cells.
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DOI：
10.1016/j.ejca.2010.02.017
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发表时间：
2010-06
影响因子：
8.4
通讯作者：
Joshi, Harish C.
中科院分区：
文献类型：
--
作者：
Aneja, Ritu;Miyagi, Tohru;Karna, Prasanthi;Ezell, Tucker;Shukla, Deep;Gupta, Meenakshi Vij;Yates, Clayton;Chinni, Sreenivasa R.;Zhau, Haiyen;Chung, Leland W. K.;Joshi, Harish C.
激素难治性前列腺癌及其骨转移和并发症仍然是治疗上的挑战。在这里，我们表明用（S）-3-（（R）-9-溴-4-甲氧基-6-甲基-5，6，7，8-四氢-[1，3]间二氧杂环戊烯[4，5-g]异喹啉-5-基）-6，7-二甲氧基异苯并呋喃-1（3 H）-酮（EM 011）（植物来源的无毒止咳生物碱诺斯卡品的溴化类似物）处理，如裸鼠中肿瘤生长的非侵入性实时生物发光成像所示，从机制上讲，体外数据表明EM 011在人前列腺癌细胞系中的抗增殖和促凋亡作用是通过损害双极纺锤体的形成来阻断细胞周期进程。G2/M期阻滞伴随有丝分裂检查点的激活，这是诱导最佳凋亡的先决条件。通过siRNA双链体减弱有丝分裂检查点导致有丝分裂停滞和随后的凋亡减少。我们的研究结果进一步证明了内在的神经细胞介导的凋亡途径的参与，最终触发半胱天冬酶驱动的EM 011诱导的凋亡。EM 011在具有频繁分裂细胞的正常组织（如肠道和骨髓）中未产生任何可检测的毒性。因此，这些数据保证了EM 011用于前列腺癌管理的进一步评价。
Hormone refractory prostate cancer, its skeletal metastasis and complications remain a therapeutic challenge. Here we show that treatment with (S)-3-((R)-9-bromo-4-methoxy-6-methyl-5,6,7,8-tetrahydro-[1,3]dioxolo[4,5-g]isoquinolin-5-yl)-6,7-dimethoxyiso-benzofuran-1(3H)-one (EM011), the brominated analog of a plant-derived non-toxic antitussive alkaloid, noscapine, achieved significant inhibition of hormone-refractory human prostate cancer implanted intratibially in the bone as shown by non-invasive, real-time bioluminescent imaging of tumor growth in nude mice. Mechanistically, in vitro data suggested that the anti-proliferative and pro-apoptotic effects of EM011 in human prostate cancer cell lines were through blockade of cell-cycle progression by impairing the formation of a bipolar spindle apparatus. The G2/M arrest was accompanied by activation of the mitotic checkpoint, a pre-requisite for induction of optimal apoptosis. Attenuation of mitotic checkpoint by siRNA duplexes led to a reduction in mitotic arrest and subsequent apoptosis. Our results further demonstrated participation of an intrinsic mitochondrially-mediated apoptotic pathway that ultimately triggered caspase-driven EM011-induced apoptosis. EM011 did not exert any detectable toxicity in normal tissues with frequently dividing cells such as the gut and bone marrow. Thus, these data warrant further evaluation of EM011 for the management of prostate cancer.
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影响因子：
3
作者：
Aneja, Ritu;Dhiman, Neerupma;Joshi, Harish C.
通讯作者：
Joshi, Harish C.
影响因子：
4
作者：
Amon, A
通讯作者：
Amon, A
影响因子：
3.5
作者：
Hsieh, CL;Xie, Z;Chung, LWK
通讯作者：
Chung, LWK
影响因子：
11.2
作者：
Aneja, R;Lopus, M;Joshi, HC
通讯作者：
Joshi, HC
DOI：
10.1196/annals.1331.056
发表时间：
2004-01-01
期刊：
VITAMIN E AND HEALTH
影响因子：
--
作者：
Jiang, Q;Wong, J;Ames, BN
通讯作者：
Ames, BN