Institute of Biological Sciences, Faculty of Science, Universiti Malaya, Jalan Profesor Diraja Ungku Aziz, Kuala Lumpur, Wilayah Persekutuan Kuala Lumpur, Malaysia.
Department of Chemistry, Faculty of Science, Universiti Malaya, Jalan Profesor Diraja Ungku Aziz, Kuala Lumpur, Wilayah Persekutuan Kuala Lumpur, Malaysia.
Planta Med. 2022 Nov;88(14):1325-1340. doi: 10.1055/a-1755-5605. Epub 2022 Jan 31.
Two iboga-vobasine bisindoles, 16'-decarbomethoxyvoacamine (1: ) and its 19,20-dihydro derivative, 16'-decarbomethoxydihydrovoacamine (2: ) from exhibited potent cytotoxicity against the human colorectal adenocarcinoma HT-29 cells in our previous studies. Bisindoles 1: and 2: selectively inhibited the growth of HT-29 cells without significant cytotoxicity to normal human colon fibroblasts CCD-18Co. Treatment with bisindoles 1: and 2: suppressed the formation of HT-29 colonies via G0/G1 cell cycle arrest and induction of mitochondrial apoptosis. Owing to its higher antiproliferative activity, bisindole 2: was chosen for the subsequent studies. Bisindole 2: inhibited the formation of HT-29 spheroids (tumor-like cell aggregates) in 3D experiments in a dose-dependent manner, while an tubulin polymerization assay and molecular docking analysis showed that bisindole 2: is a microtubule-stabilizing agent which is predicted to bind at the -tubulin subunit at the taxol-binding site. The binding resulted in the generation of ROS, which consequently activated the oxidative stress-related cell cycle arrest and apoptotic pathways, viz., JNK/p38, p21/Chk1, and p21/Rb/E2F, as shown by microarray profiling.
两种伊波加-沃巴辛双吲哚，16'-去甲氧基羰基沃卡因（1：）及其 19,20-二氢衍生物，16'-去甲氧基羰基二氢沃卡因（2：），具有潜在的细胞毒性，能够抑制人类结直肠腺癌细胞 HT-29 的生长。双吲哚 1：和 2：选择性地抑制 HT-29 细胞的生长，而对正常人类结肠成纤维细胞 CCD-18Co 没有明显的细胞毒性。双吲哚 1：和 2：处理通过 G0/G1 细胞周期阻滞和诱导线粒体凋亡来抑制 HT-29 集落的形成。由于其更高的增殖抑制活性，双吲哚 2：被选为后续研究。双吲哚 2：在 3D 实验中以剂量依赖性方式抑制 HT-29 球体（肿瘤样细胞聚集体）的形成，而微管蛋白聚合测定和分子对接分析表明，双吲哚 2：是一种微管稳定剂，预计结合在紫杉烷结合位点的 -微管蛋白亚基上。这种结合导致 ROS 的产生，从而激活与氧化应激相关的细胞周期阻滞和凋亡途径，即 JNK/p38、p21/Chk1 和 p21/Rb/E2F，如微阵列分析所示。
