Capsazepine is a specific antagonist of the transient receptor potential vanilloid 1 (TRPV1) receptor with an IC50 value of 562nM [1]. Capsazepine is a synthetic analogue of capsaicin, which is the primary pungent component found in chili peppers[2]. TRPV1 is a non-selective cation channel that participates in various physiological and pathological processes such as pain perception, temperature regulation, and inflammatory response[3]. Capsazepine serves as a therapeutic agent for pain management by acting through TRPV1. Capsazepine also exhibits anticancer and anti-inflammatory effects, making it widely used in the treatment of various diseases, including pancreatic cancer, breast cancer, pancreatitis, and neurogenic inflammation[4].
In vitro, capsazepine(0-60μM) treated human DU145 prostate cancer cells for 24h experience suppressed proliferation and enhanced apoptosis. Following a 6-hour exposure to the 1, 2.5, 5μM of capsazepine, DU145 cells demonstrated inhibition of JAK phosphorylation and STAT activation[5]. Capsazepin(0-200μM) concentration dependently triggers an immediate rise of intracellular [Ca2+] and exhibits a cytotoxic effect after 5h treatment in PC-3 prostate cells[6]. Capsazepine can also lead to a substantial programmed cell death in MDA-MB-231 cells within 48h at concentrations exceeding 25μM, and colorectal HCT116 cells at 10 or 30μM or 6h by increased ROS production[4].
In vivo, intraperitoneal injection of capsazepine at doses of 1mg/kg and 5mg/kg, 3 times/week inhibits disease progression in prostate cancer xenograft mice by reducing constitutive p-STAT3 expression and increasing PTPε protein levels in tumor tissue, comparing to the control group receiving PBS treatment[5]. Subcutaneous administration of capsazepine (3–10mg/kg) in osteosarcoma bearing mice 1h before tests can inhibit cancer hyperalgesia in a dose-dependant manner[7]. Pretreated with capsazepine at a dose of 100μmol/kg via subcutaneous injection miligate pancreatic inflammation in male Sprague-Dawley rats as the therapeutic efficacy is evaluated by pancreatic edema, myeloperoxidase (MPO) activity and histological grading [8].
References:
[1] Seabrook, G.R.,Sutton,K.G., Jarolimek,W et al. Functional Properties of the High-Affinity TRPV1 (VR1) Vanilloid Receptor Antagonist (4- Hydrox -5-iodo-3 -methoxyphenylacetate ester)Iodo-Resiniferatoxin. Journal of Pharmacology and Experimental Therapeutics. 2002.303(3), 1052–1060.
[2] Bevan S.,Hothi S.,Hughes G., et al.Capsazepine: a competitive antagonist of the sensory neurone excitant capsaicin. Br J Pharmacol. 1992 Oct;107(2):544-52.
[3] Tabrizi, A.M, Baraldi,G.P.,Baraldi S., et al.Medicinal Chemistry, Pharmacology, and Clinical Implications of TRPV1 Receptor Antagonists. Med Res Rev. 2017 Jul;37(4):936-983.
[4] Yang, M.H, Jung S.H., Gautam Sethi G., Ahn K.S.,Pleiotropic Pharmacological Actions of Capsazepine, a Synthetic Analogue of Capsaicin, against Various Cancers and Inflammatory Diseases. Molecules. 2019 Mar 12;24(5):995.
[5] Lee J.H., Kim C., Baek S.H., et al. Capsazepine inhibits JAK/STAT3 signaling, tumor growth, and cell survival in prostate cancer. Oncotarget. 2017;8:17700–17711.
[6] Huang J.K., Cheng H.H., Huang C.J., et al. Effect of capsazepine on cytosolic Ca(2+) levels and proliferation of human prostate cancer cells. Toxicology In Vitro. 2006;20:567–574.
[7] Menéndez L., Juárez L., García E , García-Suárez O, et al.Analgesic effects of capsazepine and resiniferatoxin on bone cancer pain in mice.Neurosci Lett. 2006 Jan 23;393(1):70-3.
[8] Vigna S.R., Shahid R.A., Nathan J.D., McVey D.C., Liddle R.A. Leukotriene B4 mediates inflammation via TRPV1 in duct obstruction-induced pancreatitis in rats. Pancreas. 2011;40:708–714.
Capsazepine是瞬时受体电位香草素1（TRPV1）受体的特异性拮抗剂，IC50值为562nM[1]。Capsazepine是辣椒中主要刺激性成分"辣椒素"的合成类似物[2]。TRPV1是一种非选择性的阳离子通道，它参与了疼痛感知、温度调节、炎症反应等多种生理和病理过程[3]。Capsazepine可以作为治疗疼痛的药物，通过TRPV1起作用，Capsazepine还具有抗癌和抗炎作用，使其广泛用于治疗各种疾病，包括胰腺癌、乳腺癌、胰腺炎和神经源性炎症[4]。
在体外，capsazepine（0-60μM）作用于人DU145前列腺癌细胞24h，有抑制癌细胞增殖、促进其凋亡的作用。暴露于1、2.5、5μM的capsazepine 6小时后，DU145细胞表现出JAK磷酸化和STAT激活抑制[5]。在PC-3前列腺细胞中，capsazepin（0-200μM）剂量依赖性地触发胞内[Ca2+]激增，并在处理5h后表现出细胞毒性作用[6]。用浓度超过25μM的capsazepine处理MDA-MB-231细胞48h，以及用10或30μM capsazepine处理结肠直肠HCT116细胞6小时可导致癌细胞中ROS生成增加，并最终导致大量程序性细胞死亡[4]。
在体内，capsazepine通过腹腔注射1mg/kg和5mg/kg剂量，每周3次治疗前列腺癌异种移植小鼠，与接受PBS治疗的对照组相比，capsazepine通过降低肿瘤组织中p-STAT3组成型表达和增加PTPε蛋白水平，抑制小鼠的疾病进展[5]。Capsazepine（3-10mg/kg）在测试前1h通过皮下注射骨肉瘤小鼠，能以剂量依赖性方式抑制肿瘤引起的痛觉过敏[7]。Capsazepin(100μmol/kg)预处理Sprague-Dawley大鼠胰腺炎症模型，后通过胰腺水肿、髓过氧化物酶（MPO）活性和组织学分级评价的治疗效果，发现炎症得到缓解[8]。