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首页> 外文期刊>Biochemical Pharmacology >Antitumor 1-nitroacridine derivative C-1748, induces apoptosis, necrosis or senescence in human colon carcinoma HCT8 and HT29 cells.
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Antitumor 1-nitroacridine derivative C-1748, induces apoptosis, necrosis or senescence in human colon carcinoma HCT8 and HT29 cells.

机译：抗肿瘤的1-硝基ac啶衍生物C-1748，在人结肠癌HCT8和HT29细胞中诱导凋亡，坏死或衰老。

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摘要

C-1748 is a DNA-binding agent with potent antitumor activity, especially towards prostate and colon carcinoma xenografts in mice. Here, we elucidated the nature of cellular response of human colon carcinoma HCT8 and HT29 cells to C-1748 treatment, at biologically relevant concentrations (EC(90) and their multiplicity). Cell cycle analysis showed gradual increase in HCT8 cells with sub-G1 DNA content (25% after 72h) considered as apoptotic. Hypodiploid cell population increased up to 60% upon treatment with 4x EC(90) concentration of the drug. Compared with HCT8 cells, the fraction of sub-G1 HT29 cells did not exceed 14%, even following 4-fold dose escalation. Morphological changes and biochemical markers such as: phosphatydylserine externalization, apoptotic DNA breaks, mitochondrial dysfunction and caspase activation confirmed the presence of considerable amount of apoptotic HCT8 cells but only a low amount of apoptotic HT29 cells. Next, we demonstrated that HCT8 cells surviving after exposure to C-1748 were in the state of senescence, based on altered cell morphology and expression of a pH 6-dependent beta-galactosidase. On the contrary, no beta-galactosidase staining was observed in HT29 cells after C-1748 treatment. Moreover, prolonged drug incubation (up to 168h) resulted in massive detachment of cells from culture plates, which together with Annexin V/PI results, indicated that necrosis was the main response of HT29 cells to C-1748 treatment. We also determined the ability of C-1748 to induce reactive oxygen species (ROS) in colon cancer cells and demonstrated, that generation of ROS was not essential for C-1748-induced apoptosis and cytotoxic activity of this drug.
机译：C-1748是一种DNA结合剂，具有强大的抗肿瘤活性，尤其是对小鼠的前列腺癌和结肠癌异种移植物。在这里，我们阐明了人类结肠癌HCT8和HT29细胞在生物学相关浓度（EC（90）及其多重性）下对C-1748治疗的细胞反应的本质。细胞周期分析显示，具有亚G1 DNA含量（72小时后25％）的HCT8细胞逐渐凋亡。使用4x EC（90）浓度的药物处理后，二倍体细胞数量增加了60％。与HCT8细胞相比，即使在4倍剂量递增后，sub-G1 HT29细胞的比例也不会超过14％。形态学变化和生化标记，例如：磷脂酰丝氨酸外在化，凋亡的DNA断裂，线粒体功能障碍和胱天蛋白酶激活，证实存在大量的凋亡HCT8细胞，但仅存在少量的凋亡HT29细胞。接下来，我们基于改变的细胞形态和pH 6依赖性β-半乳糖苷酶的表达，证明了暴露于C-1748后存活的HCT8细胞处于衰老状态。相反，在C-1748处理后，在HT29细胞中未观察到β-半乳糖苷酶染色。此外，长时间的药物温育（长达168h）导致细胞大量脱离培养板，这与Annexin V / PI结果一起表明坏死是HT29细胞对C-1748处理的主要反应。我们还确定了C-1748在结肠癌细胞中诱导活性氧（ROS）的能力，并证明了ROS的生成对于C-1748诱导的这种药物的凋亡和细胞毒性活性不是必需的。

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