Instituto Venezolano de Investigaciones Cientificas (IVIC), Centre for Microbiology & Cell Biology, Tumor Cell Biology Laboratory, Apartado 20632, Caracas 1020-A, Venezuela.
J Med Chem. 2010 Feb 25;53(4):1627-35. doi: 10.1021/jm901314r.
In contrast to other metal-dithiocarbamate [DEDTC] complexes, the copper-DEDTC complex is highly cytotoxic, inducing oxidative stress, preferentially in tumor cells. Because nitric oxide (NO) forms adducts with CuDEDTC, we investigated whether NO donors like S-nitroso-N-acetyl penicillamine (SNAP) or sodium nitroprusside (SNP), and nitrite, a NO decomposition product, modulate CuDEDTC cytotoxicity against human tumor cells. We show that apoptosis-associated PARP cleavage and inducible nitric oxide synthase (iNOS) down-regulation induced by nanomolar CuDEDTC, are counteracted by 50 muM SNAP, SNP, or CoCl(2), an inducer of hypoxia and NO signaling. Nitrite was stochiometrically effective in antagonizing CuDEDTC cytotoxicity and inducing shifts in the absorption spectrum of the binary complex in the 280 and 450 nm regions. Subtoxic concentrations of CuDEDTC became lethal when tumor cells were pretreated with c-PTIO, a membrane-impermeable scavenger for extracellular NO. Our results suggest that: (a) reactive oxygen species induced by CuDEDTC are scavenged by nitrite released from NO, (b) the extent of lethality of CuDEDTC is dependent on the reciprocal formation of an inactive ternary CuDEDTCNO copper-nitrosyl complex.
与其他金属-二硫代氨基甲酸盐 [DEDTC] 配合物相比，铜-DEDTC 配合物具有高度细胞毒性，诱导氧化应激，优先在肿瘤细胞中诱导。由于一氧化氮 (NO) 与 CuDEDTC 形成加合物，我们研究了一氧化氮供体如 S-亚硝基-N-乙酰青霉胺 (SNAP) 或硝普酸钠 (SNP) 以及作为一氧化氮分解产物的亚硝酸盐是否调节 CuDEDTC 对人肿瘤细胞的细胞毒性。我们表明，CuDEDTC 诱导的与细胞凋亡相关的 PARP 切割和诱导型一氧化氮合酶 (iNOS) 下调被 50 μM SNAP、SNP 或 CoCl(2) 拮抗，CoCl(2) 是缺氧和一氧化氮信号的诱导剂。亚硝酸盐在拮抗 CuDEDTC 细胞毒性和诱导二元配合物在 280 和 450nm 区域吸收光谱的变化方面具有化学计量学的有效性。当肿瘤细胞用 c-PTIO 预处理时，CuDEDTC 的亚毒性浓度会变得致命，c-PTIO 是一种用于细胞外 NO 的膜不可渗透清除剂。我们的结果表明：(a)CuDEDTC 诱导的活性氧被从 NO 释放的亚硝酸盐清除，(b)CuDEDTC 的致死程度取决于活性较低的三元 CuDEDTCNO 铜亚硝酰配合物的形成程度。
