The anticancer effects of chaetocin are independent of programmed cell death and hypoxia, and are associated with inhibition of endothelial cell proliferation.
The anticancer effects of chaetocin are independent of programmed cell death and hypoxia, and are associated with inhibition of endothelial cell proliferation.
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DOI：
10.1038/bjc.2011.522
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发表时间：
2012-01-17
影响因子：
8.8
通讯作者：
Bible, K. C.
中科院分区：
文献类型：
--
作者：
Isham, C. R.;Tibodeau, J. D.;Bossou, A. R.;Merchan, J. R.;Bible, K. C.
我们以前曾报道，毛霉素有有效和选择性的抗骨髓瘤活性，这归因于通过抑制氧化还原酶硫氧还蛋白还原酶而诱导的活性氧(ROS)；现在我们详细说明它在实体肿瘤中的作用。细胞分析、转录图谱和NCI60筛选用于评估毛壳素对实体瘤和血管内皮细胞的影响。NCI-60筛选显示，毛壳素在实体肿瘤中比在血液细胞系中更有效地抑制增殖；转录图谱显示了与诱导炎症反应和细胞死亡途径一致的特征。毛壳菌素在所有受试实体瘤细胞系中均可诱导ROS、细胞蛋白质氧化损伤和细胞凋亡，其IC50为2-10 NM(24 h)。PAN-caspase抑制剂zVAD-fmk尽管抑制线粒体膜去极化和细胞凋亡，但并不能阻止由毛霉素所诱导的细胞死亡。此外，缺乏代谢功能线粒体的Molt-4RO0细胞很容易被毛壳素杀死；此外，毛壳素诱导的细胞毒性不受自噬抑制剂或缺氧以及随后的HIF-1α上调的影响。此外，Chaetocin抑制SKOV3卵巢癌移植瘤产生较少的血管肿瘤，并抑制人脐静脉内皮细胞的增殖。毛壳素在体外和体内具有耐人寻味和广泛的抗癌作用，是进一步临床前和临床开发的有吸引力的候选药物。
We previously reported that chaetocin has potent and selective anti-myeloma activity attributable to reactive oxygen species (ROS) induction imposed by inhibition of the redox enzyme thioredoxin reductase; we now detail its effects in solid tumours. Cellular assays, transcriptional profiling and the NCI60 screen were used to assess the effects of chaetocin in solid tumour and endothelial cells. NCI-60 screening demonstrated chaetocin to even more potently inhibit proliferation in solid tumour than in haematological cell lines; transcriptional profiling revealed a signature consistent with induction of inflammatory response and cell death pathways. Chaetocin induced ROS, oxidative damage to cellular proteins and apoptosis, with 2–10 nM IC50s (24 h exposures) in all tested solid tumour cell lines. The pan-caspase inhibitor zVAD-fmk did not block chaetocin-induced cell death despite inhibiting mitochondrial membrane depolarisation and apoptosis. Further, Molt-4 rho0 cells lacking metabolically functional mitochondria were readily killed by chaetocin; in addition chaetocin-induced cytotoxicity was unaffected by autophagy inhibitors or hypoxia and consequent HIF-1α upregulation. Moreover, chaetocin inhibited SKOV3 ovarian cancer xenografts producing less vascular tumours, and inhibited human umbilical vein endothelial cell proliferation. Chaetocin has intriguing and wide-ranging in vitro and in vivo anticancer effects, and is an attractive candidate for further preclinical and clinical development.
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影响因子：
15
作者：
Kim J;Movassaghi M
通讯作者：
Movassaghi M
DOI：
10.1093/jnci/83.11.757
发表时间：
1991-06-05
期刊：
JOURNAL OF THE NATIONAL CANCER INSTITUTE
影响因子：
--
作者：
MONKS, A;SCUDIERO, D;BOYD, M
通讯作者：
BOYD, M
影响因子：
15
作者：
Iwasa, Eriko;Hamashima, Yoshitaka;Sodeoka, Mikiko
通讯作者：
Sodeoka, Mikiko
影响因子：
5.5
作者：
Freire, FDO;Kozakiewicz, Z;Paterson, RRM
通讯作者：
Paterson, RRM
影响因子：
4.5
作者：
Fang, J.;Nakamura, H.;Iyer, A. K.
通讯作者：
Iyer, A. K.