β3-Adrenoreceptor Blockade Reduces Hypoxic Myeloid Leukemic Cells Survival and Chemoresistance

Abstract

β-adrenergic signaling is known to be involved in cancer progression; in particular, beta3-adrenoreceptor (β3-AR) is associated with different tumor conditions. Currently, there are few data concerning β3-AR in myeloid malignancies. Here, we evaluated β3-AR in myeloid leukemia cell lines and the effect of β3-AR antagonist SR59230A. In addition, we investigated the potential role of β3-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 β3-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, β3-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 β3-AR as a new target and β3-AR blockade as a potential approach in myeloid leukemias.

Sympathetic Denervation Alters the Inflammatory Response of Resident Muscularis Macrophages upon Surgical Trauma and Ameliorates Postoperative Ileus in Mice

“…Notably, cSTX strongly affected gene expression levels for distinct adrenergic receptors (AR) in the muscularis externa tissue but also in sorted macrophages. Two ARs that are expressed by various immune and nonimmune cells in the GI tract [31] and regulate intestinal inflammation [32,33] are Adrb2 (β2AR) and Adrb3 (β3AR). These ARs were upregulated in the muscularis externa but strongly downregulated in the sorted MMs, indicating a compensatory response of other muscularis cells.…”

β3‐Adrenoceptor, a novel player in the round‐trip from neonatal diseases to cancer: Suggestive clues from embryo

“…In addition, β3‐AR blockade reinstated the sensitivity to doxorubicin, likely through downregulating P‐gp levels. Moreover, β3‐AR blockade reduced the expression of UCP‐2 and HIF‐1 suggesting a strict link between hypoxia, Warburg effect, and chemoresistance 145 …”

“…β3-AR role in chemoresistance was demonstrated in human myeloid leukemia cell lines, in particular in leukemia cells resistant to doxorubicin, a chemotherapy drug. 145 In chemoresistant cells, both β3-ARs and the membrane transporter P-glycoprotein (P-gp), which is involved in drug efflux, 146 increased in their expression. In addition, β3-AR blockade reinstated the sensitivity to doxorubicin, likely through downregulating P-gp levels.…”

“…Moreover, β3-AR blockade reduced the expression of UCP-2 and HIF-1 suggesting a strict link between hypoxia, Warburg effect, and chemoresistance. 145…”

Role of β3-Adrenergic Receptor in Bone Marrow Transplant as Therapeutical Support in Cancer

“…Moreover, it was seen that this switch from stemness to cell differentiation is regulated by β3-AR through a molecular interplay with sphingosine kinase 2 (SK2)/S1P receptor 2 (S1P2) axis, typically implicated in neuroblastoma biology ( 27 ). Interestingly, β3-AR expression has been reported also in human leukemia ( 28 ) where it appears to be involved in the survival of myeloid leukemia cells, especially under hypoxic conditions, to such an extent that β3-AR could be considered as a potential target also in this type of cancer, mostly to reduce chemoresistance, a phenomenon that occurs frequently in leukemic patients ( 29 ).…”