β adrenergic signaling regulates hematopoietic stem and progenitor cell commitment and therapy sensitivity in multiple myeloma

Nair, Remya; Subramaniam, Vimal; Barwick, Benjamin G; Gupta, Vikas A.; Matulis, Shannon M.; Lonial, Sagar; Boise, Lawrence H.; Nooka, Ajay K.; Muthumalaiappan, Kuzhali; Shanmugam, Mala

doi:10.3324/haematol.2022.280907

Cited by 4 publications

(1 citation statement)

References 18 publications

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“…Propranolol was shown to reduce the CTRA gene signature. In another study, BM samples from MM patients showed that propranolol can augment differentiation of HSCs into megakaryocyte-erythrocyte progenitors and reduce the number of granulocyte-monocyte progenitor cells, which are known to contribute to a pro-tumorigenic niche [ 41 ]. Together, these studies indicate that propranolol can block the negative effects of adrenergic signaling on HSC biology, induce HSC proliferation and differentiation, as well as synergize with a CXCR4 inhibitor considering the possible crosstalk between β 2 AR and CXCR4 in BM.…”

Section: Introductionmentioning

confidence: 99%

GPC-100, a novel CXCR4 antagonist, improves in vivo hematopoietic cell mobilization when combined with propranolol

Sukhtankar,

Fung,

Kim

et al. 2023

PLoS ONE

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Autologous Stem Cell Transplant (ASCT) is increasingly used to treat hematological malignancies. A key requisite for ASCT is mobilization of hematopoietic stem cells into peripheral blood, where they are collected by apheresis and stored for later transplantation. However, success is often hindered by poor mobilization due to factors including prior treatments. The combination of G-CSF and GPC-100, a small molecule antagonist of CXCR4, showed potential in a multiple myeloma clinical trial for sufficient and rapid collection of CD34+ stem cells, compared to the historical results from the standards of care, G-CSF alone or G-CSF with plerixafor, also a CXCR4 antagonist. In the present study, we show that GPC-100 has high affinity towards the chemokine receptor CXCR4, and it potently inhibits β-arrestin recruitment, calcium flux and cell migration mediated by its ligand CXCL12. Proximity Ligation Assay revealed that in native cell systems with endogenous receptor expression, CXCR4 co-localizes with the beta-2 adrenergic receptor (β2AR). Co-treatment with CXCL12 and the β2AR agonist epinephrine synergistically increases β-arrestin recruitment to CXCR4 and calcium flux. This increase is blocked by the co-treatment with GPC-100 and propranolol, a non-selective beta-adrenergic blocker, indicating a functional synergy. In mice, GPC-100 mobilized more white blood cells into peripheral blood compared to plerixafor. GPC-100 induced mobilization was further amplified by propranolol pretreatment and was comparable to mobilization by G-CSF. Addition of propranolol to the G-CSF and GPC-100 combination resulted in greater stem cell mobilization than the G-CSF and plerixafor combination. Together, our studies suggest that the combination of GPC-100 and propranolol is a novel strategy for stem cell mobilization and support the current clinical trial in multiple myeloma registered as NCT05561751 at www.clinicaltrials.gov.

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Section: Introductionmentioning

confidence: 99%