SR59230A is a potent and selective β3-adrenoceptor antagonist, with IC50 values of 40, 408, and 648nM for β3-, β1-, and β2-receptors, respectively [1]. SR59230A is a novel inhibitor of the Kir2.1 channel, with an IC50 value of 33μM[2]. SR59230A inhibits the phosphorylation and thereby the activation of the mTOR/p70S6K pathway, crosses the blood-brain barrier, and acts on β3 adrenoceptors[3-4]. SR59230A has been widely used to inhibit cancer cell progression and to develop novel combination therapies[5].
In vitro, SR59230A treatment for 72 hours significantly inhibited the proliferation of HUVEC, BRAF mutated 8505 C thyroid carcinoma cells, and U-87 cells with IC50 values of 6.45µM, 13.09µM, and 18.21µM, respectively[6]. Treatment with 10µM SR59230A for 48 hours induced apoptosis in K562, KCL22, HEL and HL60 cells under hypoxic conditions (1% O2)[7].
In vivo, SR59230A treatment via continuous intratumoral injection at a dose of 5mg/kg for 8 consecutive days led to a significant reduction in tumor volume and weight in the melanoma mouse model, and inhibited angiogenesis[8]. For a period of 5 weeks, 50µg of SR59230A (dissolved in DMSO) was injected into the tail vein every 3 days, which significantly inhibited the growth of breast cancer xenograft tumors in mice and reduced the expressions of p-mTOR S2448, p-4E-BP1 (T37/46), and p-mTOR S2481[9].
References:
[1] Kanzler S A, Januario A C, Paschoalini M A. Involvement of β3-adrenergic receptors in the control of food intake in rats[J]. Brazilian Journal of Medical and Biological Research, 2011, 44: 1141-1147.
[2] Kulzer M, Seyler C, Welke F, et al. Inhibition of cardiac Kir2. 1–2.3 channels by beta3 adrenoreceptor antagonist SR 59230A[J]. Biochemical and Biophysical Research Communications, 2012, 424(2): 315-320.
[3] Deng J, Jiang P, Yang T, et al. Targeting β3-adrenergic receptor signaling inhibits neuroblastoma cell growth via suppressing the mTOR pathway[J]. Biochemical and Biophysical Research Communications, 2019, 514(1): 295-300.
[4] Lob H E, Song J, Hurr C, et al. Deletion of p22phox-dependent oxidative stress in the hypothalamus protects against obesity by modulating β3-adrenergic mechanisms[J]. JCI insight, 2017, 2(2): e87094.
[5] Ascone M, Banella C, Amato R, et al. Abstract A048 SR59230A-induced ferroptosis sensitization of Ewing sarcoma cells via Beta-3 adrenergic receptor modulation: A novel therapeutic target[J]. Cancer Research, 2024, 84(17_Supplement): A048-A048.
[6] Bandini A, Biso L, Viaggi C, et al. Synergistic combination of the adrenergic antagonist SR59230A with common chemotherapeutic drugs and target therapies in cancer and endothelial cells[J]. Investigational New Drugs, 2025: 1-11.
[7] Calvani M, Dabraio A, Bruno G, et al. β3-adrenoreceptor blockade reduces hypoxic myeloid leukemic cells survival and Chemoresistance[J]. International Journal of Molecular Sciences, 2020, 21(12): 4210.
[8] Dal Monte M, Casini G, Filippi L, et al. Functional involvement of β3-adrenergic receptors in melanoma growth and vascularization[J]. Journal of molecular medicine, 2013, 91(12): 1407-1419.
[9] Zhou Z, Zhan J, Luo Q, et al. ADRB3 induces mobilization and inhibits differentiation of both breast cancer cells and myeloid-derived suppressor cells[J]. Cell Death & Disease, 2022, 13(2): 141.
SR59230A是一种高效、选择性的β3-肾上腺素受体拮抗剂，对β3、β1和β2受体的IC50值分别为40nM、408nM和648nM[1]。SR59230A是Kir2.1通道的新型抑制剂，IC50值为33μM[2]。SR59230A能通过抑制mTOR/p70S6K通路的磷酸化以阻断活化，并能穿过血脑屏障，作用于β3 肾上腺素受体[3-4]。SR59230A已广泛应用于抑制癌细胞进展及开发新型联合疗法[5]。
在体外，SR59230A处理72小时可显著抑制HUEVC、BRAF突变甲状腺癌细胞和U-87细胞的增殖，IC50值分别为6.45µM、13.09µM和18.21µM[6]。在低氧条件下，使用10µM的SR59230A处理K562、KCL22、HEL和HL60细胞48小时，能在缺氧条件下（1% O2）诱导细胞凋亡[7]。
在体内，连续9日每日瘤内注射5mg/kg剂量的SR59230A，可显著缩小黑色素瘤小鼠模型的肿瘤体积和重量，并抑制血管生成[8]。每3日尾静脉注射50µg剂量的的SR59230A（溶于DMSO）连续5周，能显著抑制乳腺癌移植瘤在小鼠体内的生长，并降低p-mTOR S2448、p-4E-BP1(T37/46)和p-mTOR S2481的表达水平[9]。