School of Biosciences & Biopharmaceutics and Guangdong Province Key Laboratory for Biotechnology Drug Candidates, Guangdong Pharmaceutical University, Guangzhou 510006, China; School of Pharmacy, Guangdong Pharmaceutical University, Guangzhou 510006, China.
Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, 651 Dongfeng Road East, Guangzhou, Guangdong Province, 510060, China.
Biomed Pharmacother. 2021 Jan;133:110961. doi: 10.1016/j.biopha.2020.110961. Epub 2020 Nov 12.
Indolizine derivatives have been reported for the treatment of numerous diseases. However, few studies were carried out for non-small cell lung cancer (NSCLC). We synthesized series of indolizine compounds. The results of MTT assay showed compound 8 (C8) markedly inhibited the proliferation of A549 cells, however, C8 (15, 30 μg/mL) had little cytotoxicity in other cell lines (SH-SY5Y, HepG2, and BEAS-2B cells), Hoechst staining and JC-1 staining showed that C8 induced changes in the nucleus morphology, increased the loss in mitochondrial membrane potential in A549 cells. The results of flow cytometry manifested that cell cycle of the cells was arrested in the G2 / M phase by C8, ROS levels and the proportion of apoptosis of cells increased. We performed western blotting analysis to detect the expression levels of apoptosis and cycle-related proteins. These results validated that the apoptosis of cells was triggered by endoplasmic reticulum stress (ERS) and the PI3K/Akt-mediated mitochondrial pathway collaboratively. Besides, the utilization of PI3K/Akt inhibitors and p53 inhibitors further proves the above argument and C8-induced cycle arrest of A549 cells is majorly regulated by p53. C8 induced the accumulation of ROS contents involved in mitochondrial damage. The proliferation of A549 cells was inhibited after treatment with the compound, which induced apoptosis and cycle arrest of cells. It is suggested that C8(dithiolation indolizine) is a potential candidate compound against non-small cell lung cancer.
吲哚嗪衍生物已被报道可用于治疗多种疾病。然而，针对非小细胞肺癌（NSCLC）的研究较少。我们合成了一系列吲哚嗪类化合物。MTT 检测结果表明，化合物 8（C8）能显著抑制 A549 细胞的增殖，而 C8（15、30μg/ml）对其他细胞系（SH-SY5Y、HepG2 和 BEAS-2B 细胞）的细胞毒性较小。Hoechst 染色和 JC-1 染色结果表明，C8 诱导 A549 细胞核形态发生变化，导致线粒体膜电位丧失。流式细胞术结果显示，C8 将细胞周期阻滞在 G2/M 期，细胞内 ROS 水平和凋亡比例增加。Western blot 分析检测到凋亡和细胞周期相关蛋白的表达水平。这些结果验证了细胞凋亡是由内质网应激（ERS）和 PI3K/Akt 介导的线粒体途径共同触发的。此外，PI3K/Akt 抑制剂和 p53 抑制剂的使用进一步证明了上述观点，C8 诱导的 A549 细胞周期阻滞主要受 p53 调节。C8 诱导的 ROS 含量积累涉及线粒体损伤。用该化合物处理后，A549 细胞的增殖受到抑制，导致细胞凋亡和周期阻滞。这表明 C8（二硫代吲哚嗪）是一种有潜力的非小细胞肺癌候选化合物。
