Centre for Advanced Drug Research, COMSATS University Islamabad, Abbottabad Campus, Abbottabad-22060, Pakistan.
Department of Chemistry, Faculty of Science, The University of Haripur, Haripur, KPK-22620, Pakistan.
Anticancer Agents Med Chem. 2021;21(9):1082-1091. doi: 10.2174/1871520620666200721110732.
Despite various technological advances for the treatment of cancer, the identification of new chemical entities with potent anticancer effects remain an indispensable requirement of the time due to multi-drug resistance exhibited by previously developed anticancer drugs. Particularly, the hybrid drugs incorporating two individual bioactive pharmacophores present medicinally important structural leads, thus improving the pharmacodynamic profile of the drug molecules. The antiproliferative and pro-apoptotic activity of the carbazole-chalcone hybrids on human breast and cervical cancer cells will be examined.
To overcome such complications, in the current study, we evaluated the cytotoxic effects of carbazole-chalcone hybrids on human breast adenocarcinoma (MCF-7), cervical adenocarcinoma (HeLa) cells and normal cells, i.e., Baby Hamster Kidney cells (BHK-21) using MTT (dimethyl-2-thiazolyl-2,5- diphenyl-2H-tetrazolium bromide) assay. The mechanistic studies were performed on potent compound 4g by fluorescent microscopic studies, release of Lactate Dehydrogenase (LDH) and mitochondrial membrane potential, activation of caspase-9 and -3 and flow cytometric analysis.
As revealed by MTT assay, compound 4g was identified as the most potent derivative among the tested series with IC values of 5.64 and 29.15μM against HeLa and MCF-7 cells, respectively. The results were compared with cisplatin. Fluorescent microscopic studies using 4',6-diamidino-2-phenylindole (DAPI) and Propidium Iodide (PI) staining confirmed the occurrence of apoptosis in HeLa cells treated with the most active compound 4g. Moreover, compound 4g also triggered the release of Lactate Dehydrogenase (LDH) in treated HeLa and MCF-7 cells while a fluorescence assay displayed a remarkable increase in the activity of caspase-9 and -3. Moreover, flow cytometric results revealed that compound 4g caused G/G arrest in the treated HeLa cells.
Our results demonstrated that the compound 4g possesses chemotherapeutic properties against breast cancer and cervical adenocarcinoma cells, thus warranting further research to test the anticancer potential of this compound at preclinical and clinical level.
尽管癌症治疗技术不断进步，但由于先前开发的抗癌药物表现出多药耐药性，因此仍需要识别具有强大抗癌作用的新化学实体。特别是，结合两个单独的生物活性药效团的杂合药物具有重要的药用结构先导，从而改善了药物分子的药效学特征。将检测咔唑-查尔酮杂合体对人乳腺癌和宫颈癌细胞的增殖抑制和促凋亡活性。
为了克服这些并发症，在本研究中，我们使用 MTT（二甲基噻唑基-2,5-二苯基-2H-四唑溴盐）测定法评估了咔唑-查尔酮杂合体对人乳腺癌腺癌细胞（MCF-7）、宫颈癌腺癌细胞（HeLa）和正常细胞（即仓鼠肾细胞（BHK-21））的细胞毒性作用。通过荧光显微镜研究、乳酸脱氢酶（LDH）和线粒体膜电位释放、半胱天冬酶-9 和 -3 的激活以及流式细胞术分析，对有效化合物 4g 进行了机制研究。
MTT 测定结果表明，化合物 4g 是所测试系列中最有效的衍生物，对 HeLa 和 MCF-7 细胞的 IC 值分别为 5.64 和 29.15μM。结果与顺铂进行了比较。使用 4'，6-二脒基-2-苯基吲哚（DAPI）和碘化丙啶（PI）染色的荧光显微镜研究证实了用最活性化合物 4g 处理的 HeLa 细胞中发生了凋亡。此外，化合物 4g 还触发了在处理的 HeLa 和 MCF-7 细胞中乳酸脱氢酶（LDH）的释放，而荧光测定显示半胱天冬酶-9 和 -3 的活性显着增加。此外，流式细胞术结果表明，化合物 4g 导致处理的 HeLa 细胞中 G/G 期阻滞。
我们的结果表明，化合物 4g 具有针对乳腺癌和宫颈癌腺癌细胞的化疗特性，因此需要进一步研究以在临床前和临床水平上测试该化合物的抗癌潜力。
