Targeting the β₂‐adrenergic receptor increases chemosensitivity in multiple myeloma by induction of apoptosis and modulating cancer cell metabolism

Abstract

While multi‐drug combinations and continuous treatment have become standard for multiple myeloma, the disease remains incurable. Repurposing drugs that are currently used for other indications could provide a novel approach to improve the therapeutic efficacy of standard multiple myeloma treatments. Here, we assessed the anti‐tumor effects of cardiac drugs called β‐blockers as a single agent and in combination with commonly used anti‐myeloma therapies. Expression of the β2‐adrenergic receptor correlated with poor survival outcomes in patients with multiple myeloma. Targeting the β2‐adrenergic receptor (β2AR) using either selective or non‐selective β‐blockers reduced multiple myeloma cell viability, and induced apoptosis and autophagy. Blockade of the β2AR modulated cancer cell metabolism by reducing the mitochondrial respiration as well as the glycolytic activity. These effects were not observed by blockade of β1‐adrenergic receptors. Combining β2AR blockade with the chemotherapy drug melphalan or the proteasome inhibitor bortezomib significantly increased apoptosis in multiple myeloma cells. These data identify the therapeutic potential of β2AR‐blockers as a complementary or additive approach in multiple myeloma treatment and support the future clinical evaluation of non‐selective β‐blockers in a randomized controlled trial. © 2022 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.

Ginsenoside Rh4 inhibits the malignant progression of multiple myeloma and induces ferroptosis by regulating SIRT2

“…At present, multi‐drug combination chemotherapy is still the main first‐line treatment option for this disease. Compared with single drug therapy, the efficacy of multi‐drug combination therapy is increased, but at the same time, the adverse effects are also increased 13 . Therefore, it is particularly important to seek for new therapeutic means to increase the treatment efficacy and improve the life quality of MM patients.…”

Repurposing beta-blockers for combinatory cancer treatment: effects on conventional and immune therapies

“…Similarly, another study illustrated the possibility of using BBs as a supplementary therapy as it induces cell cycle arrest and promote apoptosis in human colorectal cancer cells ( Coelho et al, 2015 ). As of 2023, a new study demonstrated that the concurrent use of PRO with chemotherapy, exhibits antitumor properties when administered alongside chemotherapy in the context of multiple myeloma cells ( Satilmis et al, 2023 ).…”

“…Furthermore, another study aimed to assess the antitumor effects of NSBB and SBB in multiple myeloma when combined with chemotherapy. It was concluded that BBs that targets β2-AR from PRO to ICI affected multiple myeloma cell viability and induced apoptosis and autophagy ( Satilmis et al, 2023 ).…”

“…Impact varies on the specific type of SBB to impact OS (Farhoumand et al, 2023). Metoprolol Comparable effects to NSBB if β2 inhibition (ICI) occurs (Cuesta et al, 2019;Del Vecchio et al, 2023;Satilmis et al, 2023) Comparable to NSBB if β2 inhibition (ICI) occurs (Cuesta et al, 2019;Del Vecchio et al, 2023;Satilmis et al, 2023)…”

Targeting mTOR signaling pathways in multiple myeloma: biology and implication for therapy

“…These fibers release norepinephrine that will bind to the β2 adrenergic receptor (β2AR), found on the different cell types in the BM [ 105 ]. We found that β2AR is a poor prognostic factor in MM and that the β2AR blocker propranolol inhibited mTOR activation which led to increased apoptosis in MM cells [ 106 ].…”