Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, St. John's University, Queens, NY, 11439, USA.
Department of Pharmaceutical Chemistry, University of Karachi, Karachi, 75270, Pakistan.
Int J Biochem Cell Biol. 2019 May;110:21-28. doi: 10.1016/j.biocel.2019.02.004. Epub 2019 Feb 19.
Colorectal cancer is the third leading cause of cancer related deaths in the United States. Currently, Irinotecan, a topoisomerase I inhibitor, is an approved anti-cancer drug for the treatment of patients with advanced or recurrent colorectal cancer. Considering low response rate and events of high toxicity caused by irinotecan, we evaluated a series of thirteen thiazolyl hydrazone derivatives of 1-indanone for their potential antineoplastic activity and four compounds showed promising anti-cancer activity against most of the tested colon cancer cell lines with IC values ranging from 0.41 ± 0.19 to 6.85 ± 1.44 μM. It is noteworthy that the compound, N-Indan-1-ylidene-N'-(4-Biphenyl-4-yl-thiazol-2-yl)-hydrazine (ITH-6) is found to be more effective than irinotecan against colon cancer cells, HT-29, COLO 205, and KM 12. Mechanistic studies reveal that ITH-6 arrests these cancer cell lines in G2/M phase of the cell cycle, induces apoptosis and causes an increase in ROS level with a significant reduction in the GSH level. The mechanism of inhibition relates to the inhibition of tubulin polymerization in the mitotic phase. These findings suggest that ITH-6 is a novel drug candidate for the treatment of colorectal cancer.
结直肠癌是美国癌症相关死亡的第三大主要原因。目前，拓扑异构酶 I 抑制剂伊立替康是一种已批准的抗癌药物，用于治疗晚期或复发性结直肠癌患者。考虑到伊立替康的低反应率和高毒性事件，我们评估了一系列 1-茚酮的十三噻唑基腙衍生物的潜在抗肿瘤活性，其中四种化合物对大多数测试的结肠癌细胞系显示出有希望的抗癌活性，IC 值范围为 0.41±0.19 至 6.85±1.44 μM。值得注意的是，化合物 N-茚-1-亚基-N'-(4-联苯-4-基-噻唑-2-基)-腙（ITH-6）对结肠癌细胞 HT-29、COLO 205 和 KM 12 的作用比伊立替康更有效。机制研究表明，ITH-6 将这些癌细胞系阻滞在细胞周期的 G2/M 期，诱导细胞凋亡并导致 ROS 水平升高，同时 GSH 水平显著降低。抑制机制与有丝分裂期微管蛋白聚合的抑制有关。这些发现表明 ITH-6 是治疗结直肠癌的一种新型候选药物。
