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Blocking β-adrenergic receptor signaling enhances the sensitivity of AML to MCL-1 inhibitor S63845
Wei Kuang1, Chenxing Zeng1, Qingqing Xie1
1Department of Clinical Pharmacology, Xiangya Hospital, Central South University, 87 Xiangya Road, Changsha 410008, PR China; Institute of Clinical Pharmacology, Central South University, Hunan Key Laboratory of Pharmacogenetics, 110 Xiangya Road, Changsha 410078, PR China; Engineering Research Center of Applied Technology of Pharmacogenomics, Ministry of Education, 110 Xiangya Road, Changsha 410078, PR China; National Clinical Research Center for Geriatric Disorders, 87 Xiangya Road, Changsha 410008, Hunan, PR China.
Aims:
Myeloid cell leukemia-1 (MCL-1) critically drives acute myeloid leukemia (AML) pathogenesis and represents a promising therapeutic target. Despite potent preclinical activity, the clinical efficacy of S63845, a selective MCL-1 inhibitor, remains limited in AML trials. We therefore aimed to develop novel combination strategies enhancing S63845 sensitivity.
Methods:
Effects of β-AR modulation on AML cell viability, S63845 sensitivity, and BCL-2 family protein expression were investigated. Isoproterenol (ISO) and β-AR blocker (propranolol, atenolol, ICI-118551) were assessed using CCK-8 assays and Western blotting. Propranolol's ability to enhance S63845 sensitivity was evaluated both in vitro (via CCK-8, apoptosis flow cytometry, S63845-resistant cell generation) and in vivo (using subcutaneous xenograft models). Western blotting analyzed BCL-2 family protein expression following single or combined treatment with propranolol and S63845. Mechanistic insight was preliminarily explored by establishing MCL-1 stable knockdown cells.
Results:
(1) β-AR agonists (Iso/Epi) upregulated MCL-1, driving proliferation and S63845 resistance, reversed by β2-AR blockade; (2) Propranolol synergized with S63845 in vitro and vivo; (3) Propranolol counteracts S63845-induced MCL-1 upregulation; (4) MCL-1 knockdown enhanced S63845 sensitivity.
Conclusions:
Stress induced catecholamines confer S63845 resistance in AML through β-AR signaling. Critically, β2-AR blockade by propranolol downregulates MCL-1 expression, potentiating S63845 sensitivity in vitro and in vivo. Our findings establish pharmacological β-AR blockade as a promising strategy to overcome resistance in MCL-1-targeted therapy by abrogating compensatory MCL-1 upregulation.
Insights
Beta-adrenergic receptor (β-AR) signaling promotes resistance to MCL-1 inhibitors like S63845 in acute myeloid leukemia (AML). Blocking β2-AR with propranolol enhances S63845 sensitivity by downregulating MCL-1, offering a novel therapeutic strategy.
Area of Science:
- Hematology
- Oncology
- Pharmacology
Background:
- Myeloid cell leukemia-1 (MCL-1) is crucial in acute myeloid leukemia (AML) pathogenesis.
- MCL-1 inhibitors like S63845 show preclinical promise but have limited clinical efficacy in AML.
- Novel strategies are needed to enhance sensitivity to MCL-1 targeted therapy.
Purpose of the Study:
- To investigate the role of beta-adrenergic receptor (β-AR) signaling in AML and its impact on S63845 sensitivity.
- To develop combination strategies to overcome S63845 resistance in AML.
Main Methods:
- Assessed effects of β-AR agonists and blockers on AML cell viability and S63845 sensitivity.
- Utilized CCK-8 assays, Western blotting, apoptosis flow cytometry, and xenograft models.
- Investigated BCL-2 family protein expression and MCL-1 knockdown effects.
Main Results:
- β-AR agonists (Isoproterenol, Epinephrine) increased MCL-1, promoting proliferation and S63845 resistance.
- β2-AR blockade using propranolol reversed MCL-1 upregulation and S63845 resistance.
- Propranolol synergized with S63845 in vitro and in vivo, downregulating MCL-1.
Conclusions:
- Stress-induced catecholamines confer S63845 resistance in AML via β-AR signaling.
- Pharmacological β-AR blockade, specifically with propranolol, downregulates MCL-1 and potentiates S63845 efficacy.
- β-AR blockade represents a promising strategy to overcome resistance in MCL-1-targeted AML therapy.
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