除了细胞毒性,COX-2酶的抑制剂已证明对癌症治疗具有重要的附加作用(例如肿瘤细胞的放射增敏作用和细胞抗增殖作用);然而,其他炎症相关酶5-LOX抑制剂的抑制与抗癌活性之间的关系仍未得到很好的理解。在我们的研究中,我们在3种癌细胞系(HCT116,HT-29和BxPC-3)和1种健康细胞系(MRC-5)上测试了我们组之前提出的13种COX-2和5-LOX抑制剂(1-13)的细胞毒性.化合物3、5、6和7显示出中等的细胞毒性,但对癌细胞系具有良好的选择性。IC50值在22.99-51.66µM(HCT116细胞系)的范围内,8.63-41.20µM(BxPC-3细胞系)和24.78-81.60µM(HT-29细胞系;化合物7>100µM)。与测试相比,市售COX-2和5-LOX抑制剂,细胞毒性和选择性均增加。在辐射处理中加入化合物6和7显示HT-29细胞系的细胞增殖最显著降低(p<0.001)。通过使用SW620细胞系的伤口愈合测定来测试最佳双COX-2和5-LOX抑制剂(化合物1、2、3和5)的抗迁移潜力。化合物1和3作为具有最有效作用的化合物(相对伤口闭合率为3.20%(24小时),化合物1的5.08%(48h)和3.86%(24h),7.68%(48h)的化合物3)。考虑到所有这些结果,化合物3是生物活性最佳的化合物,具有最佳的双重COX-2和5-LOX抑制活性,对测试的癌细胞系具有良好的选择性,显著的细胞抗迁移潜力和在治疗剂量缺乏毒性作用。
Apart from
cytotoxicity, inhibitors of the COX-2 enzyme have demonstrated additional effects important for cancer treatment (such as radiosensitization of tumor cells and cell antimigratory effects); however, the relationship between the inhibition of other inflammation-related enzyme 5-LOX inhibitors and anticancer activity is still not well understood. In our study, the
cytotoxicity of thirteen COX-2 and 5-LOX inhibitors previously presented by our group (1-13) was tested on three cancer cell lines (HCT 116, HT-29 and BxPC-3) and one healthy cell line (MRC-5). Compounds 3, 5, 6 and 7 showed moderate
cytotoxicity, but good selectivity towards cancer cell lines. IC50 values were in the range of 22.99-51.66 µM (HCT 116 cell line), 8.63-41.20 µM (BxPC-3 cell line) and 24.78-81.60 µM (HT-29 cell line; compound 7 > 100 µM). In comparison to tested, commercially available COX-2 and 5-LOX inhibitors, both
cytotoxicity and selectivity were increased. The addition of compounds 6 and 7 to irradiation treatment showed the most significant decrease in cell proliferation of the HT-29 cell line (p < 0.001). The antimigratory potential of the best dual COX-2 and 5-LOX inhibitors (compounds 1, 2, 3 and 5) was tested by a wound-healing assay using the SW620 cell line. Compounds 1 and 3 were singled out as compounds with the most potent effect (relative wound closure was 3.20% (24 h), 5,08% (48 h) for compound 1 and 3.86% (24 h), 7.68% (48 h) for compound 3). Considering all these results, compound 3 stood out as the compound with the most optimal biological activity, with the best dual COX-2 and 5-LOX inhibitory activity, good selectivity towards tested cancer cell lines, significant cell antimigratory potential and a lack of toxic effects at therapeutic doses.