Activation of mitochondrial-associated apoptosis signaling pathway and inhibition of PI3K/Akt/mTOR signaling pathway by voacamine suppress breast cancer progression

PI3K/AKT/mTOR通路 细胞凋亡 癌症研究 蛋白激酶B 细胞周期 化学 细胞生长 乳腺癌 细胞周期蛋白D1 癌细胞 活性氧 癌症 生物 医学 内科学 生物化学
作者
Yi Y. Zuo,Chaozheng Zhang,Qing Ren,Yao Chen,Li Xiao,Ji-Rui Yang,Hongxiang Li,Wentao Tang,Hing‐Man Ho,Chen Sun,Meimei Li,Bo Ren,Jianbo Xiao,Mao-lin Wang,Jun Lü
出处
期刊:Phytomedicine [Elsevier]
卷期号:99: 154015-154015 被引量:28
标识
DOI:10.1016/j.phymed.2022.154015
摘要

Breast cancer is one of the malignant tumors with the highest morbidity and mortality rate. Numerous efficient anti-breast cancer drugs are being derived from the development of natural products. Voacamine (VOA), a bisindole alkaloid isolated from Voacanga africana Stapf, possesses various pharmacological and biological activities.In this study, we investigated the efficacy of VOA against breast cancer cells and elucidated the underlying mechanisms in vitro and in vivo.Human breast cancer cell line MCF-7 and mouse breast cancer cell line 4T1 were used to study the underlying anti-cancer mechanisms of VOA. The proliferation was detected by MTT, colony formation, cell proliferation and wound-healing migration assays. Flow cytometry was utilized to determine the level of reactive oxygen species (ROS) cell-cycle, apoptosis and mitochondrial membrane potential. The target proteins were analyzed by Western blot. Molecular docking was performed and scored by AutoDock. Subcutaneous cancer models in mice were established to evaluate the anticancer effects in vivo.Our results demonstrated that VOA selectively suppressed breast cancer MCF-7 and 4T1 cells proliferation with IC50 values of 0.99 and 1.48 μM, and significantly inhibited the migration and colony formation of tumor cells. Furthermore, the cell cycle was arrested in the S phase with the decreased expression levels of CDK2, Cyclin A and Cyclin E. Additionally, exposure to VOA dose-dependently brought about dose-dependently the loss of mitochondrial membrane potential (Δψm) and amassment of reactive oxygen species (ROS), resulting in the initiation of the intrinsic apoptotic pathway. Western blot analysis unveiled that VOA significantly activated mitochondrial-associated apoptosis and obviously suppress the PI3K/Akt/mTOR pathway via modulation of related protein expression levels in both tumor cell lines. In tumor-bearing mouse models, administration of VOA dose-dependently inhibited the tumor growth without causing apparent toxicities.These findings revealed the novel properties of VOA in promoting apoptosis of breast cancer cells by activating mitochondrial-associated apoptosis signaling pathway and inhibiting PI3K/Akt/mTOR signaling pathway and significantly decreasing tumor size without detecting appreciable toxicity. In summary, the present results demonstrated VOA could be an encouraging drug candidate to cure breast cancer, exhibiting an effective method to exploit unique drugs from natural components.
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