Oridonin Synergistically Enhances the Pro-Apoptotic Effect of Venetoclax on Acute Myeloid Leukemia Cells by Inhibiting AKT Signaling

Background: Acute myeloid leukemia (AML) is a recurrence-prone hematologic malignancy. The advent of molecularly targeted therapies provides new opportunities to enhance the effectiveness of AML treatments. Venetoclax, a selective inhibitor of the anti-apoptotic protein Bcl-2, has shown promising results; however, resistance often arises due to elevated expression of the Mcl-1 protein, among other factors. Overcoming this resistance to improve therapeutic outcomes is a pressing issue that requires further investigation. Studies have demonstrated that oridonin, by inhibiting AKT signaling that regulates Mcl-1 expression, can effectively suppress tumor cell growth. This study aims to investigate whether oridonin can synergistically enhance the anti-leukemic effects of venetoclax and explore the underlying mechanisms behind this effect.

Methods: In vitro experiments were performed to evaluate the effects of the combination of oridonin and venetoclax on AML cell proliferation, apoptosis, cell cycle distribution, and mitochondrial membrane potential. Transcriptome sequencing was used to elucidate the molecular mechanisms underlying the synergistic induction of AML cell apoptosis by the combination therapy. Western blotting and reverse transcription quantitative polymerase chain reaction (RT-qPCR) techniques were used to validate the findings. Additionally, an AML mouse model was established to observe the synergistic anti-AML effects of venetoclax combined with oridonin in vivo.

Results: Both venetoclax and oridonin individually exhibited inhibitory effects on AML cell proliferation, resulted in cell cycle arrest, and induced cell apoptosis. Moreover, combination of the two drugs resulted in a synergistic effect. We also observed that oridonin inhibited AKT phosphorylation, upregulated the expression of Bim and Bax proteins, facilitated Mcl-1 degradation, and enhanced the apoptotic effects of venetoclax in AML cells. Finally, in vivo experiments demonstrated that the combination of oridonin and venetoclax effectively inhibited the growth of AML xenograft tumors in mice and prolonged the survival time of tumor-bearing mice.

Conclusions: Oridonin and venetoclax synergistically promote AML cell apoptosis by inhibiting AKT signaling.

 

Comments:

**Title: Synergistic Induction of Apoptosis in Acute Myeloid Leukemia Cells by Oridonin and Venetoclax through Inhibition of AKT Signaling**

**Abstract:**

**Background:** Acute myeloid leukemia (AML) is a recurrent hematologic malignancy often resistant to treatments due to various factors, including elevated Mcl-1 expression. Venetoclax, a Bcl-2 inhibitor, has shown promise, but resistance mechanisms limit its effectiveness. Oridonin, an AKT signaling inhibitor, has demonstrated anti-tumor properties. This study explores the synergistic effects of oridonin and venetoclax on AML cells and investigates the underlying mechanisms.

**Methods:** In vitro experiments assessed AML cell proliferation, apoptosis, cell cycle distribution, and mitochondrial membrane potential upon treatment with oridonin and venetoclax. Transcriptome sequencing elucidated the molecular mechanisms. Validation was done through Western blotting and RT-qPCR. An AML mouse model was employed to observe in vivo effects.

**Results:** Oridonin and venetoclax individually inhibited AML cell proliferation, induced apoptosis, and caused cell cycle arrest. The combination exhibited a synergistic effect. Oridonin inhibited AKT phosphorylation, upregulated Bim and Bax, facilitated Mcl-1 degradation, and enhanced venetoclax-induced apoptosis. In vivo, the combination suppressed AML xenograft tumors and prolonged survival in mice.

**Conclusions:** Oridonin and venetoclax synergistically induce apoptosis in AML cells by inhibiting AKT signaling. This study provides insights into a potential therapeutic strategy for AML, overcoming resistance and enhancing treatment effectiveness.

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