Department of Biophysics, Panjab University, Chandigarh, 160014, India.
Departments of Pharmacology, Pennsylvania State University College of Medicine, Hershey, USA.
Sci Rep. 2023 Jun 8;13(1):9301. doi: 10.1038/s41598-023-36555-w.
Colorectal cancer (CRC) is a multistep disorder resulting from genetic and epigenetic genome changes. It is the third most common malignancy in developed nations accounting for roughly 600,000 deaths annually. Persistent gut inflammation, as observed in inflammatory bowel disease (IBD), is a key risk factor for CRC development. From an epigenetic viewpoint, the pharmacological inhibition of HDACs using HDAC inhibitors such as SAHA has emerged as a suitable anticancer strategy in the recent past. However, the clinical success of these strategies is limited and has risk factors associated with their uses. Thus, considering the critical involvement of epigenetic regulation of key molecular mechanisms in carcinogenesis as well as HDAC inhibitory and anti-tumorigenic properties of Selenium (Se), we aimed to explore the potentially safer and enhanced chemotherapeutic potential of a Se derivative of SAHA namely SelSA-1, in an experimental model of colitis-associated experimental cancer (CAC) model and mechanism involved therein. The in vitro study indicated improved efficiency, specificity, and better safety margin in terms of lower IC value of SelSA-1 than SAHA in both NIH3T3 (9.44 and 10.87 µM) and HCT 115 (5.70 and 7.49 µM) cell lines as well on primary colonocytes (5.61 and 6.30 µM) respectively. In an in vivo experimental model, SelSA-1 efficiently demonstrated amelioration of the multiple plaque lesions (MPLs), tumor burden/incidence, and modulation of various histological and morphological parameters. Further, redox-mediated alterations in apoptotic mediators suggested induction of cancer cell apoptosis by SelSA-1. These findings indicate the enhanced chemotherapeutic and pro-resolution effects of SelSA-1 in part mediated through redox modulation of multiple epigenetic and apoptotic pathways.
结直肠癌（CRC）是一种多步骤的疾病，是由遗传和表观遗传基因组变化引起的。它是发达国家中第三常见的恶性肿瘤，每年导致约 60 万人死亡。炎症性肠病（IBD）中观察到的持续性肠道炎症是 CRC 发展的关键危险因素。从表观遗传学的角度来看，使用 HDAC 抑制剂（如 SAHA）抑制 HDAC 已成为最近的一种合适的抗癌策略。然而，这些策略的临床成功是有限的，并与它们的使用相关的风险因素。因此，考虑到关键的分子机制的表观遗传调控以及硒（Se）的 HDAC 抑制和抗肿瘤特性在致癌作用中的关键作用，我们旨在探索一种 SAHA 的 Se 衍生物 SelSA-1 在结肠炎相关实验性癌症（CAC）模型及其相关机制中的潜在更安全和增强的化疗潜力。体外研究表明，SelSA-1 在 NIH3T3（9.44 和 10.87µM）和 HCT 115（5.70 和 7.49µM）细胞系以及原代结肠细胞（5.61 和 6.30µM）中的效率、特异性和更好的安全性都优于 SAHA，IC 值较低。在体内实验模型中，SelSA-1 有效地证明了对多发性斑块病变（MPLs）、肿瘤负担/发生率的改善，并调节了各种组织学和形态学参数。此外，凋亡介质的氧化还原介导改变表明 SelSA-1 通过诱导癌细胞凋亡来发挥作用。这些发现表明 SelSA-1 的增强化疗和促解决作用部分是通过对多种表观遗传和凋亡途径的氧化还原调节来介导的。
