Malojirao Vikas H, Girimanchanaika Swamy S, Shanmugam Muthu K, Sherapura Ankith, Metri Prashant K, Vigneshwaran Vellingiri, Chinnathambi Arunachalam, Alharbi Sulaiman Ali, Rangappa Shobith, Mohan Chakrabhavi Dhananjaya, Prabhakar Bettadathunga T, Rangappa Kanchugarakoppal S
Molecular Biomedicine Laboratory, Postgraduate Department of Studies and Research in Biotechnology, Sahyadri Science College, Kuvempu University, Shivamogga, Karnataka 577203, India.
Laboratory of Chemical Biology, Department of Studies in Organic Chemistry, University of Mysore, Manasagangotri, Mysore, Karnataka 570006, India.
Biomedicines. 2020 Sep 21;8(9):368. doi: 10.3390/biomedicines8090368.
Lung cancer is the leading type of malignancy in terms of occurrence and mortality in the global context. STAT3 is an oncogenic transcription factor that is persistently activated in many types of human malignancies, including lung cancer. In the present report, new oxadiazole conjugated indazoles were synthesized and examined for their anticancer potential in a panel of cancer cell lines. Among the new compounds, 2-(3-(6-chloro-5-methylpyridin-3-yl)phenyl)-5-(1-methyl-1H-indazol-3-yl)-1,3,4-oxadiazole (CHK9) showed consistently good cytotoxicity towards lung cancer cells with IC values ranging between 4.8-5.1 µM. The proapoptotic effect of CHK9 was further demonstrated by Annexin-FITC staining and TUNEL assay. In addition, the effect of CHK9 on the activation of STAT3 in lung cancer cells was examined. CHK9 reduced the phosphorylation of STAT3 in a dose-dependent manner. CHK9 had no effect on the activation and expression of JAK2 and STAT5. It also reduced the STAT3-dependent luciferase reporter gene expression. CHK9 increased the expression of proapoptotic (p53 and Bax) proteins and decreased the expression of the antiapoptotic (Bcl-2, Bcl-xL, BID, and ICAM-1) proteins. CHK9 displayed a significant reduction in the number of tumor nodules in the in vivo lung cancer model with suppression of STAT3 activation in tumor tissues. CHK9 did not show substantial toxicity in the normal murine model. Overall, CHK9 inhibits the growth of lung cancer cells and tumors by interfering with the STAT3 signaling pathway.
在全球范围内，肺癌在发病率和死亡率方面是主要的恶性肿瘤类型。信号转导和转录激活因子3（STAT3）是一种致癌转录因子，在包括肺癌在内的多种人类恶性肿瘤中持续激活。在本报告中，合成了新的恶二唑共轭吲唑，并在一组癌细胞系中检测了它们的抗癌潜力。在这些新化合物中，2-(3-(6-氯-5-甲基吡啶-3-基)phenyl)-5-(1-甲基-1H-吲唑-3-基)-1,3,4-恶二唑（CHK9）对肺癌细胞始终表现出良好的细胞毒性，IC值在4.8 - 5.1 μM之间。Annexin-FITC染色和TUNEL检测进一步证明了CHK9的促凋亡作用。此外，研究了CHK9对肺癌细胞中STAT3激活的影响。CHK9以剂量依赖的方式降低了STAT3的磷酸化。CHK9对JAK2和STAT5的激活和表达没有影响。它还降低了STAT3依赖的荧光素酶报告基因表达。CHK9增加了促凋亡（p53和Bax）蛋白的表达，降低了抗凋亡（Bcl-2、Bcl-xL、BID和ICAM-1）蛋白的表达。在体内肺癌模型中，CHK9显著减少了肿瘤结节的数量，同时抑制了肿瘤组织中STAT3的激活。在正常小鼠模型中，CHK9没有表现出明显的毒性。总体而言，CHK9通过干扰STAT3信号通路抑制肺癌细胞和肿瘤的生长。
