Keshari Amit K, Singh Ashok K, Kumar Umesh, Raj Vinit, Rai Amit, Kumar Pranesh, Kumar Dinesh, Maity Biswanath, Nath Sneha, Prakash Anand, Saha Sudipta
Department of Pharmaceutical Sciences, Babasaheb Bhimrao Ambedkar University.
Centre of Biomedical Research, SGPGIMS Campus.
Drug Des Devel Ther. 2017 Oct 13;11:2981-2995. doi: 10.2147/DDDT.S143075. eCollection 2017.
5H-benzo[h]thiazolo[2,3-b]quinazoline scaffold is known to have an antitumor effect on certain types of malignancies; however, its effect on hepatocellular carcinoma (HCC) remains unclear. Previously, we reported -toluenesulfonic acid-promoted syntheses, molecular modeling and in vitro antitumor activity of 5H-benzo[h]thiazolo[2,3-b]quinazoline against human hepatoma (Hep-G2) cells where compounds and were found to be potent inhibitors among the series. In continuation to our previous effort to develop novel therapeutic strategies for HCC treatment, here we investigated the in vivo antitumor activity and the mechanism underlying the effects of and in N-nitrosodiethylamine (NDEA)-induced HCC using male Wistar rats. NDEA was administered weekly intraperitoneally at a dose of 100 mg/kg for 6 weeks. Various physiological and morphological changes, oxidative parameters, liver marker enzymes and cytokines were assessed to evaluate the antitumor effect of and . In addition, proton nuclear magnetic resonance-based serum metabolomics were performed to analyze the effects of and against HCC-induced metabolic alterations. Significant tumor incidences with an imbalance in carcinogen metabolizing enzymes and cellular redox status were observed in carcinogenic rats. Tumor inhibitory effects of and were noted by histopathology and biochemical profiles in NDEA-induced hepatic cancer. Compounds and had a potential role in normalizing the elevated levels of inflammatory mediators such as interleukin-1β (IL-1β), IL-2, IL-6 and IL-10. At molecular level, the real-time quantitative reverse-transcribed polymerase chain reaction analysis revealed that and attenuated the gene overexpression in hepatic cancer. Further, orthogonal partial least squares discriminant analysis scores plot demonstrated a significant separation of and -treated groups from carcinogen control group. Both the compounds have potential to restore the imbalanced metabolites due to HCC, signifying promising hepatoprotective activities. All these findings suggested that and could be potential drug candidates to treat HCC.
已知5H-苯并[h]噻唑并[2,3-b]喹唑啉支架对某些类型的恶性肿瘤具有抗肿瘤作用；然而，其对肝细胞癌（HCC）的作用仍不清楚。此前，我们报道了对甲苯磺酸促进的5H-苯并[h]噻唑并[2,3-b]喹唑啉的合成、分子建模及其对人肝癌（Hep-G2）细胞的体外抗肿瘤活性，其中化合物 和 被发现是该系列中的强效抑制剂。为了继续我们之前开发HCC治疗新策略的努力，在此我们使用雄性Wistar大鼠研究了化合物 和 在N-亚硝基二乙胺（NDEA）诱导的HCC中的体内抗肿瘤活性及其作用机制。NDEA每周腹腔注射一次，剂量为100 mg/kg，共注射6周。评估各种生理和形态学变化、氧化参数、肝脏标志物酶和细胞因子，以评价化合物 和 的抗肿瘤作用。此外，进行基于质子核磁共振的血清代谢组学分析，以分析化合物 和 对HCC诱导的代谢改变的影响。在致癌大鼠中观察到显著的肿瘤发生率以及致癌物代谢酶和细胞氧化还原状态的失衡。通过组织病理学和生化分析发现化合物 和 对NDEA诱导的肝癌具有肿瘤抑制作用。化合物 和 在使白细胞介素-1β（IL-1β）、IL-2、IL-6和IL-10等炎症介质升高的水平正常化方面具有潜在作用。在分子水平上，实时定量逆转录聚合酶链反应分析表明，化合物 和 减弱了肝癌中 基因的过表达。此外，正交偏最小二乘判别分析得分图显示，化合物 和 处理组与致癌物对照组有显著分离。这两种化合物都有潜力恢复由HCC导致的代谢失衡，表明它们具有有前景的肝脏保护活性。所有这些发现表明，化合物 和 可能是治疗HCC的潜在候选药物。
