(4-氟苯基)噻唑烷-4- 1对CHO-K1细胞的遗传毒性评价

J. Mamilla, Kalpana Javvaji, Kavya Lekha Sunkara, U. Kosurkar, R. Kumbhare, S. Misra
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摘要

4-噻唑烷酮是具有多种药理作用的五元杂环化合物。在之前的研究中,我们报道了一系列新合成的具有不同官能团的4-噻唑烷酮衍生物,它们对卵巢癌(SKOV3)和宫颈癌(HeLa)癌细胞具有抗癌活性。其中,(4-氟苯基)噻唑烷-4-酮(4-TH)对SKOV3具有较强的细胞毒活性,IC50值为12.3 μM。然而,也发现它对正常细胞(CHO-K1)具有极大的毒性,IC50为7.5 μM。在考虑将其用于癌症研究之前,全面了解其对正常细胞的潜在遗传毒性作用是至关重要的。本研究以正常中国仓鼠卵巢细胞CHO-K1为实验对象,对4-TH的体外细胞遗传毒性进行了研究。参考4-TH的IC50,我们选择3种亚致死浓度(2、5和7.5 μM)处理CHO-K1细胞24 h(一个细胞周期持续时间),评估其诱导染色体畸变的剂量依赖性,并按照标准方案检测4-TH对细胞分裂、微核诱导电位和细胞周期阻滞特性的影响。结果表明,4-TH对正常细胞具有高度毒性,与对照组相比,3种亚致死浓度的4-TH均导致染色体畸变数(P < 0.001)、微核形成(P < 0.01)和细胞分裂率(有丝分裂指数)的变化(P < 0.05)显著增加。此外,G1期细胞数量显著增加,表明所有浓度的4-TH均可诱导细胞凋亡。4-TH是一种强效的细胞毒性药物,其细胞毒性、致裂性和非优生性的评估无疑将为确定其安全性和作为抗癌药物的潜力提供关键信息。
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Evaluation of genotoxicity of (4-fluorophenyl) thiazolidin-4-one in CHO-K1 cells
4-thiazolidinones are five-membered heterocyclic ring compounds with diverse pharmacological impacts. In a previous study, we reported a series of newly synthesized derivatives of 4-thiazolidinones with different functional groups, which exhibited anticancer activity against ovarian (SKOV3) and cervical (HeLa) cancer cell lines. Among these derivatives, (4-fluorophenyl) thiazolidin-4-one (4-TH) demonstrated potent cytotoxic activity against SKOV3, with an IC50 value of 12.3 μM. However, it was also found to be extremely toxic to normal cells (CHO-K1) with an IC50 of 7.5 μM. Before considering its use in cancer research, it is crucial to gain a comprehensive understanding of its potential genotoxic effects on normal cells. In this study, we aimed to assess the in vitro cytogenetic toxicity of 4-TH using normal Chinese hamster ovary cells (CHO-K1). Referring to the IC50 of 4-TH, we selected three sub-lethal concentrations (2, 5, and 7.5 μM) and treated CHO-K1 cells for 24 h (one cell cycle duration) to estimate its dose-dependent induction of chromosome aberrations, and examine the effect of 4-TH on cell division, micronucleus induction potential and cell cycle arrest properties following standard protocols. The results showed that 4-TH was highly toxic to normal cells, as all three sublethal concentrations caused a statistically significant increase in the number of chromosomal aberrations (P < 0.001), formation of micronuclei (P < 0.01), and changes in the rate of cell division (mitotic index) (P < 0.05) compared to control. In addition, there was a significant increase in the number of cells in the G1 phase, indicating that all concentrations of 4-TH tested induced apoptosis. The evaluation of the cytotoxic, clastogenic, and aneugenic properties of 4-TH, a potent cytotoxic agent, will undoubtedly provide critical information for determining its safety and potential as an anticancer drug.
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