1. Carvedilol exhibits anti-acute T lymphoblastic leukemia effect in vitro and in vivo via inhibiting β-ARs signaling pathway.
- Author
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Xu, Yanpeng, Li, Jiahuan, Luo, Yan, Ma, Jinhua, Huang, Pei, Chen, Yan, and He, Zhixu
- Subjects
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CARVEDILOL , *CELLULAR signal transduction , *LYMPHOBLASTIC leukemia , *JAK-STAT pathway , *CELL cycle - Abstract
An increasing number of studies have focus upon β-adrenergic receptor blockers and their anti-tumor effects. However, the use of Carvedilol (CVD), the third generation β-AR blocker, has not been explored for use against T-ALL. In this study, the level of β-ARs was explored in pediatric T-ALL patients. Moreover, the antitumor effects of CVD against T-ALL were assessed in vitro and in vivo , and the underlying mechanisms were investigated. The viability of T-ALL cells following CVD treatment was detected using a CCK-8 assay, and the apoptotic and cell cycle effects were measured using flow cytometry. The protein levels of β-ARs, cAMP, Epac, JAK2, STAT3, p-STAT3, PI3K, p-PI3K, AKT, p -AKT, mTOR, cyclin D1, PCNA, and cleaved caspase-3 were assessed by Western blotting. In vivo experiments were used to investigate the effect of CVD on T-ALL growth in mice. The results indicated that β-ARs were highly expressed in the newly diagnosed T-ALL cells when compared to those in the control group (P < 0.05). In vitro , CVD significantly inhibited T-ALL cell viability, promoted apoptosis and blocked the G0/G1 phase of cell cycle. After CVD treatment, the protein levels of β-ARs, cAMP, Epac, PI3K, p-PI3K, AKT, p -AKT, mTOR, JAK2, STAT3, p-STAT3, cyclin D1 and PCNA were significantly downregulated (P < 0.05); whereas cleaved caspase-3 was significantly upregulated (P < 0.05). In vivo , the volume and weight of the xenograft tumors were significantly decreased in the CVD group (P < 0.05). CVD promoted xenograft tumor apoptosis and reduced the proportion of CEM-C1 cells in murine peripheral blood and bone marrow (P < 0.05). Our results demonstrate that β-ARs are expressed in T-ALL. CVD has a strong antitumor effect against T-ALL and inhibits β-AR associated signaling pathways. Therefore, CVD may provide a potential therapy for T-ALL. • The expression of β-ARs in patients with T-ALL and T-ALL cells was first discovered. • β-adrenergic receptors are positive regulators of T-ALL viability. • We find for the first time that carvedilol has a strong anti T-ALL effect. • Carvedilol can inhibit T-ALL cells proliferation and promotes apoptosis. • Carvedilol can inhibit cAMP/Epac, PI3K/AKT/mTOR and JAK2/STAT3 signaling pathways. [ABSTRACT FROM AUTHOR]
- Published
- 2023
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