Antiproliferative and proapoptotic activities of pyranoxanthenones, pyranothioxanthenones and their pyrazole-fused derivatives in HL-60 cells.
Antiproliferative and proapoptotic activities of pyranoxanthenones, pyranothioxanthenones and their pyrazole-fused derivatives in HL-60 cells.
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发表时间：
2006-07
影响因子：
2
通讯作者：
E. Perchellet;M. M. Ward-M.;A. Skaltsounis;I. Kostakis;Nicole Pouli;P. Marakos;J. Perchellet
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作者：
E. Perchellet;M. M. Ward-M.;A. Skaltsounis;I. Kostakis;Nicole Pouli;P. Marakos;J. Perchellet
合成的吡喃并噻吨酮、吡喃并噻吨酮及其吡唑稠合衍生物与DNA结合，阻断细胞周期的G2 + M期并在体外抑制腹水和实体瘤细胞系的增殖，测试了它们在HL-60细胞系统中诱导凋亡的能力。材料与方法体外检测肿瘤细胞代谢、凋亡诱导和线粒体通透性转换（MPT）的各种标志物，以评价药物的细胞毒性。结果所有这些化合物，尤其是吡唑稠合的吡喃吨酮7、8和10，在3-5 μ M范围内有效，并且比吡喃吨酮更有效，在第2天和第4天降低HL-60细胞的增殖。这些抗肿瘤药物抑制DNA合成在2小时的关系，他们的能力，阻止细胞摄取的嘌呤和嘧啶核苷在15分钟内。intermucleosomal DNA片段，细胞凋亡的晚期标志物，诱导浓度依赖性的方式7和10在24小时。聚（ADP-核糖）聚合酶-1（PARP-1）裂解，细胞致力于凋亡所需的早期事件，在12小时内检测到7和10处理的HL-60细胞。在HL-60细胞中，7和10在9 h内诱导了起始caspase-2和-9以及效应caspase-3的活性，这与caspase级联负责PARP-1切割的事实雅阁。在用7和10处理的HL-60细胞中，在9小时内也检测到线粒体细胞色素c（Cyt c）的释放，这与Cyt c是激活caspase-9的凋亡触发剂的事实一致。然而，7和10既没有引起线粒体跨膜电位的快速崩溃，也没有引起与MPT相关的线粒体肿胀。结论吡唑并吡喃吨酮类化合物是一种与DNA相互作用的抗增殖药物，在细胞和无细胞系统中不直接作用于线粒体而诱导内源性凋亡。
BACKGROUND Synthetic pyranoxanthenones, pyranothioxanthenones and their pyrazole-fused derivatives, which bind to DNA, block the G2 + M-phases of the cell cycle and inhibit the proliferation of ascitic and solid tumor cell lines in vitro, were tested for their ability to induce apoptosis in the HL-60 cell system. MATERIALS AND METHODS Various markers of tumor cell metabolism, apoptosis induction and mitochondrial permeability transition (MPT) were assayed in vitro to evaluate drug cytotoxicity. RESULTS All these compounds, and especially the pyrazole-fused pyranoxanthenones 7, 8 and 10, which were effective in the 3-5 microM range and were more potent than the pyranoxanthenones, reduced the proliferation of HL-60 cells at 2 and 4 days. These antitumor drugs inhibited DNA synthesis at 2 h in relation to their ability to block the cellular uptake of purine and pyrimidine nucleosides within 15 min. Internmucleosomal DNA fragmentation, a late marker of apoptosis, was induced in a concentration-dependent manner by 7 and 10 at 24 h. Poly(ADP-ribose) polymerase-1 (PARP-1) cleavage, an early event required for cells committed to apoptosis, was detected within 12 h in HL-60 cells treated with 7 and 10. In accord with the fact that the caspase cascade is responsible for PARP-1 cleavage, 7 and 10 induced the activities of initiator caspases-2 and -9 and effector caspase-3 within 9 h in HL-60 cells. The release of mitochondrial cytochrome c (Cyt c) was also detected within 9 h in HL-60 cells treated with 7 and 10, consistent with the fact that Cyt c is the apoptotic trigger that activates caspase-9. However, 7 and 10 neither caused the rapid collapse of mitochondrial transmembrane potential, nor the mitochondrial swelling linked to MPT. CONCLUSION Pyrazole-fused pyranoxanthenones are DNA-interacting antiproliferative drugs that do not directly target mitochondria in cell and cell-free systems to induce the intrinsic pathway of apoptosis.