Department of Biotechnology and Cell Biology, Medical College, University of Information Technology and Management in Rzeszow, Sucharskiego 2, 35-225 Rzeszow, Poland.
Department of Pharmaceutical, Organic and Bioorganic Chemistry, Danylo Halytsky Lviv National Medical University, Pekarska 69, Lviv 79010, Ukraine; Department of Organic Chemistry and Pharmacy, Lesya Ukrainka Volyn National University, Volya Avenue 13, 43025 Lutsk, Ukraine.
Bioorg Chem. 2022 Nov;128:106075. doi: 10.1016/j.bioorg.2022.106075. Epub 2022 Aug 5.
Development of cancer drug-resistance is still an ongoing problem in the modern anticancer treatment. Therefore, there is a need to search for a new active substance, which may become a potential anticancer agent. 4-Thiazolidinones are well-described substances with cytotoxicity against cancer cells in vitro. Therefore, the aim of this study was to evaluate the effect of two 4-thiazolidinone-based derivatives (Les-2769 and Les-3266) on the PPARγ-dependent cytotoxicity in normal human skin fibroblasts (BJ) and squamous cell carcinoma (SCC-15) in vitro. The data obtained showed a cytotoxic effect of Les-2769 and Les-3266 used in micromolar concentrations on SCC-15 and BJ cells, manifesting by a decrease in the metabolic activity, an increase in the release of lactate dehydrogenase, and caspase-3 activity. The co-treatment of the cells with Les-3266 and an antagonist (GW9662) or an agonist (rosiglitazone) of the PPARγ receptor induced changes in the above-mentioned parameters in the BJ and SCC-15 cells, compared to the Les-3266 alone exposure; this was not found in the Les-2769-treated cells. The further analysis of the compounds indicated changes in the expression of the PPARγ, KI67, and NF-κB genes. Moreover, the tested compounds caused an increase in the level of PPARγ mRNA expression in a similar way to rosiglitazone in SCC-15, which may indicate the affinity of the compounds for PPARγ. Molecular docking is consistent with experimental in vitro data about the potential agonistic activity of Les-2769 and Les-3266 towards PPARγ receptors. Summarizing, the anticancer effect of both compounds was observed in the SCC-15 cells in vitro; moreover, the mechanism of action of Les-3266 in cells is mediated probably by interaction with the PPARγ receptor pathway, which needs in-depth study.
癌症药物耐药性的发展仍然是现代抗癌治疗中的一个持续存在的问题。因此，需要寻找新的活性物质，这些物质可能成为潜在的抗癌药物。4-噻唑烷酮类是具有体外细胞毒性的描述良好的物质。因此，本研究的目的是评估两种基于 4-噻唑烷酮的衍生物（Les-2769 和 Les-3266）对正常人类皮肤成纤维细胞（BJ）和鳞状细胞癌细胞（SCC-15）体外 PPARγ依赖性细胞毒性的影响。研究结果表明，Les-2769 和 Les-3266 在微摩尔浓度下对 SCC-15 和 BJ 细胞具有细胞毒性作用，表现为代谢活性降低、乳酸脱氢酶释放增加和 caspase-3 活性增加。用 Les-3266 与 PPARγ 受体的拮抗剂（GW9662）或激动剂（罗格列酮）共同处理细胞，与单独用 Les-3266 处理相比，会引起 BJ 和 SCC-15 细胞上述参数的变化，但在 Les-2769 处理的细胞中未发现这种变化。对化合物的进一步分析表明，PPARγ、KI67 和 NF-κB 基因的表达发生了变化。此外，与罗格列酮类似，测试的化合物在 SCC-15 中引起 PPARγmRNA 表达水平的增加，这可能表明化合物对 PPARγ的亲和力。分子对接与实验体外数据一致，表明 Les-2769 和 Les-3266 对 PPARγ 受体具有潜在的激动活性。总之，在体外 SCC-15 细胞中观察到两种化合物的抗癌作用；此外，Les-3266 在细胞中的作用机制可能是通过与 PPARγ 受体途径相互作用介导的，这需要进一步研究。
