Lipophilic aroylhydrazone chelator HNTMB and its multiple effects on ovarian cancer cells.
Lipophilic aroylhydrazone chelator HNTMB and its multiple effects on ovarian cancer cells.
复制标题
DOI：
10.1186/1471-2407-10-72
复制
发表时间：
2010-02-25
期刊：
影响因子：
3.8
通讯作者：
Brard L
中科院分区：
文献类型：
--
作者：
Kim KK;Lange TS;Singh RK;Brard L
金属螯合剂作为一种潜在的抗癌药物受到了广泛的关注。然而，螯合剂的作用往往仅仅与它们与铁结合的能力有关，而对其他痕量金属的潜在络合作用尚未进行充分的研究。在本研究中，我们评估了包括新型化合物HNTMB在内的不同亲脂性芳酰肼螯合剂(AHC)对不同卵巢癌细胞株(SKOV-3、OVCAR-3、NUTU-19)的影响。用MTS细胞毒试验和NCI60细胞生长筛选法检测细胞活性。通过Western Blot分析、荧光显微镜和TUNEL法检测细胞的凋亡情况。流式细胞仪分析细胞周期调控和细胞内ROS的检测HNTMB具有较高的细胞毒性(IC50200-400 nM)，与已开发的AHC(oVtBBH，HNtBBH，StBBH/206，HNTh2H/315，HNI/311；IC500.8-6μM)或抗癌药物去铁胺(IC5012-25μM)相比。在NCI60肿瘤细胞系筛选中，HNTMB表现出明显的生长抑制作用，其特异性取决于所研究的细胞系(GI50，10 NM-2.4μM)。在SKOV-3卵巢癌细胞中，HNTMB处理导致染色质断裂，激活外在和内在的凋亡途径，并特异性下调Bc l-2。HNTMB通过G2/M期阻滞导致SKOV-3细胞周期延迟。HNTMB对不同氧化状态的铁、铜均有络合作用。与铜的络合作用通过产生活性氧物种(ROS)而导致高细胞毒性，而药物的铁络合物处理既不会引起细胞毒性，也不会增加ROS水平。本报告提示，非络合型HNTMB作为细胞内痕量金属的螯合剂和细胞毒性的HNTMB/铜络合物都有可能成为治疗卵巢肿瘤和其他实体肿瘤的潜在药物。
Metal chelators have gained much attention as potential anti-cancer agents. However, the effects of chelators are often linked solely to their capacity to bind iron while the potential complexation of other trace metals has not been fully investigated. In present study, we evaluated the effects of various lipophilic aroylhydrazone chelators (AHC), including novel compound HNTMB, on various ovarian cancer cell lines (SKOV-3, OVCAR-3, NUTU-19). Cell viability was analyzed via MTS cytotoxicity assays and NCI60 cancer cell growth screens. Apoptotic events were monitored via Western Blot analysis, fluorescence microscopy and TUNEL assay. FACS analysis was carried out to study Cell Cycle regulation and detection of intracellular Reactive Oxygen Species (ROS) HNTMB displayed high cytotoxicity (IC50 200-400 nM) compared to previously developed AHC (oVtBBH, HNtBBH, StBBH/206, HNTh2H/315, HNI/311; IC50 0.8-6 μM) or cancer drug Deferoxamine, a hexadentate iron-chelator (IC50 12-25 μM). In a NCI60 cancer cell line screen HNTMB exhibited growth inhibitory effects with remarkable differences in specificity depending on the cell line studied (GI50 10 nM-2.4 μM). In SKOV-3 ovarian cancer cells HNTMB treatment led to chromatin fragmentation and activation of the extrinsic and intrinsic pathways of apoptosis with specific down-regulation of Bcl-2. HNTMB caused delayed cell cycle progression of SKOV-3 through G2/M phase arrest. HNTMB can chelate iron and copper of different oxidation states. Complexation with copper lead to high cytotoxicity via generation of reactive oxygen species (ROS) while treatment with iron complexes of the drug caused neither cytotoxicity nor increased ROS levels. The present report suggests that both, non-complexed HNTMB as a chelator of intracellular trace-metals as well as a cytotoxic HNTMB/copper complex may be developed as potential therapeutic drugs in the treatment of ovarian and other solid tumors.
登录
查看更多内容
影响因子：
3.8
作者：
BOYD, MR;PAULI, KD
通讯作者：
PAULI, KD
影响因子：
7.4
作者：
Hoke, EM;Maylock, CA;Shacter, E
通讯作者：
Shacter, E
影响因子：
2.2
作者：
CHAN, A;WONG, F;ARUMANAYAGAM, M
通讯作者：
ARUMANAYAGAM, M
DOI：
10.1016/s0020-7292(03)90118-4
发表时间：
2003-10-01
影响因子：
3.8
作者：
Heintz, APM;Odicino, F;Pecorelli, S
通讯作者：
Pecorelli, S
影响因子：
5.8
作者：
Buss, JL;Neuzil, J;Ponka, P
通讯作者：
Ponka, P