?3-Adrenoreceptor Blockade Reduces Hypoxic Myeloid Leukemic Cells Survival and Chemoresistance.

ABSTRACT: ?-adrenergic signaling is known to be involved in cancer progression; in particular, beta3-adrenoreceptor (?3-AR) is associated with different tumor conditions. Currently, there are few data concerning ?3-AR in myeloid malignancies. Here, we evaluated ?3-AR in myeloid leukemia cell lines and the effect of ?3-AR antagonist SR59230A. In addition, we investigated the potential role of ?3-AR blockade in doxorubicin resistance. Using flow cytometry, we assessed cell death in different in vitro myeloid leukemia cell lines (K562, KCL22, HEL, HL60) treated with SR59230A in hypoxia and normoxia; furthermore, we analyzed ?3-AR expression. We used healthy bone marrow cells (BMCs), peripheral blood mononuclear cells (PBMCs) and cord blood as control samples. Finally, we evaluated the effect of SR59230A plus doxorubicin on K562 and K562/DOX cell lines; K562/DOX cells are resistant to doxorubicin and show P-glycoprotein (P-gp) overexpression. We found that SR59230A increased cancer cell lines apoptosis especially in hypoxia, resulting in selective activity for cancer cells; moreover, ?3-AR expression was higher in malignancies, particularly under hypoxic condition. Finally, we observed that SR59230A plus doxorubicin increased doxorubicin resistance reversion mainly in hypoxia, probably acting on P-gp. Together, these data point to ?3-AR as a new target and ?3-AR blockade as a potential approach in myeloid leukemias.

SUBMITTER: Calvani M 

PROVIDER: S-EPMC7352890 | biostudies-literature | 2020 Jun

REPOSITORIES: biostudies-literature