State Key Laboratory of Southwestern Chinese Medicine Resources, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, China.
Institute for Advancing Translational Medicine in Bone & Joint Diseases, School of Chinese Medicine, Hong Kong Baptist University, 999077, Hong Kong Special Administrative Region of China; Department of Orthopaedics and Traumatology, Li Ka Shing Faculty of Medicine, The University of Hong Kong, 999077, Hong Kong Special Administrative Region of China.
Pharmacol Res. 2022 Oct;184:106415. doi: 10.1016/j.phrs.2022.106415. Epub 2022 Aug 25.
Colorectal cancer (CRC), among the most aggressive and prevailing neoplasms, is primarily treated with chemotherapy. Voacamine (VOA), a novel bisindole natural product, possesses a variety of conspicuous pharmacological activities. Within the current research, we evaluated in vitro and in vivo the anticancer efficacy of VOA against CRC and its potential mechanisms. Our results illustrated that VOA concentrationdependently suppressed the proliferation and migration of CT26 and HCT116 cells as correspondingly indicated by IC values of 1.38 ± 0.09 μM and 4.10 ± 0.14 μM. Furthermore, treatment of VOA also suppressed tumor cell colony formation, escalated the late-stage apoptosis rate of tumor cells, and evoked cell cycle of CT26 and HCT116 cells arrest inhibition in G2-M and G0-G1 phases, respectively. Meanwhile, VOA markedly disrupted the mitochondrial membrane potential eliciting mitochondrial dysfunction, decreased ATP production, and intermediated an enhanced accumulation of intracellular reactive oxygen species with a concentration-dependent pattern, accompanied by elevated expression levels of pro-apoptotic related protein Bax, Cyt-C, cleaved caspases 3/8/9 and by diminished Bcl-2, Bid, PRAP and caspases 3/8/9 expression. Further mechanistic studies revealed VOA treatment suppressed the EGFR/PI3K/Akt pathway with the evidence of the decreased phosphorylation proteins of EGFR, PI3K, Akt, and downstream proteins of p-mTOR, p-NF-kB, and p-P70S6. Additionally, molecular dynamics simulations further displayed VOA could enter the EGFR pocket followed by multiple mutual interaction effects. Interestingly, the EGFR activator (NSC228155) could slack the inhibitory capability of VOA on the EGFR/PI3K/Akt pathway as well as VOA-induced impairment of mitochondrial function. Finally, administration of VOA (15, 30 mg/kg every 2 days, i.p., for 16 days) in CT26 syngeneic mice dose-dependently suppressed the neoplastic development without appreciable organ toxicities. Taken together, our study demonstrated that VOA may be a prospective therapeutic agent for the treatment of CRC.
结直肠癌（CRC）是最具侵袭性和普遍性的肿瘤之一，主要采用化疗治疗。Voacamine（VOA）是一种新型双吲哚天然产物，具有多种显著的药理学活性。在当前的研究中，我们评估了 VOA 对 CRC 的体外和体内抗癌疗效及其潜在机制。我们的结果表明，VOA 浓度依赖性地抑制 CT26 和 HCT116 细胞的增殖和迁移，IC 值分别为 1.38±0.09μM 和 4.10±0.14μM。此外，VOA 治疗还抑制肿瘤细胞集落形成，增加肿瘤细胞晚期凋亡率，并分别诱导 CT26 和 HCT116 细胞周期阻滞在 G2-M 和 G0-G1 期。同时，VOA 显著破坏线粒体膜电位，引发线粒体功能障碍，减少 ATP 产生，并以浓度依赖的方式介导细胞内活性氧的积累增加，同时伴有促凋亡相关蛋白 Bax、Cyt-C、cleaved caspases 3/8/9 的表达水平升高，Bcl-2、Bid、PRAP 和 caspases 3/8/9 的表达水平降低。进一步的机制研究表明，VOA 治疗抑制了 EGFR/PI3K/Akt 通路，表现为 EGFR、PI3K、Akt 的磷酸化蛋白及其下游蛋白 p-mTOR、p-NF-kB 和 p-P70S6 的表达减少。此外，分子动力学模拟进一步显示 VOA 可以进入 EGFR 口袋，随后发生多种相互作用效应。有趣的是，EGFR 激活剂（NSC228155）可以减弱 VOA 对 EGFR/PI3K/Akt 通路的抑制作用以及 VOA 诱导的线粒体功能障碍。最后，在 CT26 同基因小鼠中，以 15、30mg/kg 每 2 天腹腔注射（i.p.）16 天的剂量给予 VOA，可剂量依赖性地抑制肿瘤生长，而无明显的器官毒性。综上所述，我们的研究表明 VOA 可能是治疗 CRC 的一种有前途的治疗药物。
