Carvedilol exhibits anti-acute T lymphoblastic leukemia effect in vitro and in vivo via inhibiting fl-ARs signaling pathway

An increasing number of studies have focus upon fl-adrenergic receptor blockers and their anti-tumor effects. However, the use of Carvedilol (CVD), the third generation fl-AR blocker, has not been explored for use against T-ALL. In this study, the level of fl-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 un-derlying 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 fl-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 fl-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 fl-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 fl-ARs are expressed in T-ALL. CVD has a strong anti-tumor effect against T-ALL and inhibits fl-AR associated signaling pathways. Therefore, CVD may provide a potential therapy for T-ALL.(c) 2022 Elsevier Inc. All rights reserved.