Phytomedicine : international journal of phytotherapy and phytopharmacology · 2025
Voacamine initiates the PI3K/mTOR/Beclin1 pathway to induce autophagy and potentiate apoptosis in acute myeloid leukemia.
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Cao Yuening, Wang Yan, Chen Ying, Zhang Xuejian, Zuo Yi, Ge Xian, Sun Chen, Ren Bo, Liu Yilan, Wang Maolin, Lu Jun
Аннотация
BACKGROUND: Acute myeloid leukemia (AML) is notoriously prevalent as a malignant hematological neoplasm, and commonly prescribed combination chemotherapeutic treatments invariably involve unanticipated toxicities. Therefore, identifying potential single agent with definitive multi-target and multi-pathway anti-tumor properties is an emerging strategy for the effective treatment of AML.
PURPOSE: The present study aimed to investigate how voacamine (VOA) regulated apoptosis and autophagy to suppress the progression of AML.
METHODS: Molecular docking, western blot, CTESA, gene silencing, and immunohistochemistry were employed to demonstrate the in vivo and in vitro anti-AML capacity of VOA and to elucidate the mechanism by which VOA coordinately regulates autophagy and apoptosis.
RESULTS: Mechanistically, VOA was identified as a direct target for PI3K to suppress the PI3K/Akt/mTOR signaling pathway, thereby triggering autophagic cell death and mitochondrial pathway apoptosis in AML cells. Additionally, VOA bound and enabled Beclin1, a pivotal protein in the autophagy and apoptosis regulation, further inducing autophagy and intensifying the apoptotic process, prompting the dual pathway of AML cell death. Autophagy induced by VOA, especially the autophagosomes generation, was an essential process for apoptosis. Moreover, mTOR inhibition contributed to the Beclin1 accumulation, which, in combination with the direct Beclin1 stimulation by VOA, dramatically elevated autophagy level in AML cells. Furthermore, overexpressed Beclin1 was cleaved by Caspase protease to augment Bax expression, to promote Cyt-C release from mitochondria, and to initiate a Caspase cascade to profoundly deepen apoptosis in the mitochondrial pathway. Inspiringly, in vivo, the enhanced autophagy level in tumor tissues conversely facilitated VOA to exert its anti-AML capability.
CONCLUSION: VOA was initially identified as a novel apoptosis and autophagy activator to trigger dual-pathway programmed cell death in AML cells by targeting the regulation of the PI3K/Akt/mTOR signaling pathway and activating Beclin1.
PURPOSE: The present study aimed to investigate how voacamine (VOA) regulated apoptosis and autophagy to suppress the progression of AML.
METHODS: Molecular docking, western blot, CTESA, gene silencing, and immunohistochemistry were employed to demonstrate the in vivo and in vitro anti-AML capacity of VOA and to elucidate the mechanism by which VOA coordinately regulates autophagy and apoptosis.
RESULTS: Mechanistically, VOA was identified as a direct target for PI3K to suppress the PI3K/Akt/mTOR signaling pathway, thereby triggering autophagic cell death and mitochondrial pathway apoptosis in AML cells. Additionally, VOA bound and enabled Beclin1, a pivotal protein in the autophagy and apoptosis regulation, further inducing autophagy and intensifying the apoptotic process, prompting the dual pathway of AML cell death. Autophagy induced by VOA, especially the autophagosomes generation, was an essential process for apoptosis. Moreover, mTOR inhibition contributed to the Beclin1 accumulation, which, in combination with the direct Beclin1 stimulation by VOA, dramatically elevated autophagy level in AML cells. Furthermore, overexpressed Beclin1 was cleaved by Caspase protease to augment Bax expression, to promote Cyt-C release from mitochondria, and to initiate a Caspase cascade to profoundly deepen apoptosis in the mitochondrial pathway. Inspiringly, in vivo, the enhanced autophagy level in tumor tissues conversely facilitated VOA to exert its anti-AML capability.
CONCLUSION: VOA was initially identified as a novel apoptosis and autophagy activator to trigger dual-pathway programmed cell death in AML cells by targeting the regulation of the PI3K/Akt/mTOR signaling pathway and activating Beclin1.