Arenobufagin is a natural bufadienolide compound extracted from toad venom. Arenobufagin can induce apoptosis and autophagy by inhibiting the PI3K/Akt/mTOR signaling pathway and suppress tumor metastasis by downregulating β-catenin to inhibit epithelial-mesenchymal transition (EMT)[1-2]. Arenobufagin can be used in studies related to various cancers, such as liver cancer, prostate cancer, and gastric cancer[3-4].
In vitro, treatment of HepG2 cells with Arenobufagin (6–50nM) for 24 hours, Arenobufagin significantly inhibited cell proliferation and induced autophagy-dependent ferroptosis, manifested as mitochondrial shrinkage, lipid ROS accumulation, decreased levels of GSH and T-SOD, and downregulation of Nrf2 and COX-2 protein expression via the p62-Keap1-Nrf2 pathway[5]. In AGS and MKN-45 gastric cancer cells treated with Arenobufagin (40nM) in combination with Cisplatin (28.37µM) for 24 hours, Arenobufagin significantly enhanced the effect of Cisplatin, inhibiting cell viability, migration, and colony formation, inducing G2/M phase arrest and apoptosis, and activating alkaliptosis by downregulating CA9 and upregulating IKBKB and NF-κB/p65, accompanied by reduced expression of MMP-2/MMP-9 and increased expression of E-cadherin[6].
In vivo, intraperitoneal injection of Arenobufagin (3.2mg/kg/day and 6.4mg/kg/day) in tumor-bearing (SW1990 cells) nude mice (administered every other day starting from day 7 after cell inoculation for 24 days), Arenobufagin significantly inhibited tumor growth, reduced tumor volume and weight, and induced changes in the expression of apoptosis- and autophagy-related proteins in tumor tissues[7]. In tumor-bearing (HCT116 cells) NOD/SCID mice, intraperitoneal injection of Arenobufagin (0.5mg/kg/day, 1mg/kg/day, and 2mg/kg/day) (administered daily starting from day 1 after tail vein cell inoculation for 32 days), Arenobufagin significantly reduced the number of lung metastatic nodules and inhibited colorectal cancer lung metastasis[8].
References:
[1] Dong Q, Turdu G, Akber Aisa H, et al. Arenobufagin, isolated from Bufo viridis toad venom, inhibits A549 cells proliferation by inducing apoptosis and G2/M cell cycle arrest. Toxicon. 2024 Mar;240:107641.
[2] Zhang DM, Liu JS, Deng LJ, et al. Arenobufagin, a natural bufadienolide from toad venom, induces apoptosis and autophagy in human hepatocellular carcinoma cells through inhibition of PI3K/Akt/mTOR pathway. Carcinogenesis. 2013 Jun;34(6):1331-42.
[3] Shang Z, Fan Y, Xi S, et al. Arenobufagin enhances T-cell anti-tumor immunity in colorectal cancer by modulating HSP90β accessibility. Phytomedicine. 2024 Jun;128:155497.
[4] Chen K, Li A, Wang J, et al. Arenobufagin causes ferroptosis in human gastric cancer cells by increasing rev-erbα expression. J Tradit Complement Med. 2022 Nov 8;13(1):72-80.
[5] Yang Y, Liu C, Wang M, et al. Arenobufagin regulates the p62-Keap1-Nrf2 pathway to induce autophagy-dependent ferroptosis in HepG2 cells. Naunyn Schmiedebergs Arch Pharmacol. 2024 Jul;397(7):4895-4909.
[6] Liu C, Li D, Wang J, et al. Arenobufagin increases the sensitivity of gastric cancer to cisplatin via alkaliptosis. Heliyon. 2023 Oct 19;9(11):e21110.
[7] Wei X, Yang J, Mao Y, et al. Arenobufagin Inhibits the Phosphatidylinositol 3-kinase/Protein Kinase B/Mammalian Target of Rapamycin Pathway and Induces Apoptosis and Autophagy in Pancreatic Cancer Cells. Pancreas. 2020 Feb;49(2):261-272.
[8] Wang M, Hu S, Yang J, et al. Arenobufagin inhibits lung metastasis of colorectal cancer by targeting c-MYC/Nrf2 axis. Phytomedicine. 2024 May;127:155391.
Arenobufagin是一种从蟾蜍毒液中提取的天然bufadienolide类化合物，Arenobufagin可通过抑制PI3K/Akt/mTOR信号通路诱导细胞凋亡和自噬，并通过下调β-catenin抑制上皮-间质转化（EMT）来抑制肿瘤转移[1-2]。Arenobufagin可用于肝癌、前列腺癌、胃癌等多种癌症的相关研究[3-4]。
在体外，Arenobufagin（6-50nM）处理HepG2细胞24小时，Arenobufagin显著抑制细胞增殖，并诱导自噬依赖的铁死亡，表现为线粒体皱缩、脂质ROS积累、GSH和T-SOD水平下降，同时通过p62-Keap1-Nrf2通路下调Nrf2和COX-2蛋白表达[5]。Arenobufagin（40nM）联合Cisplatin（28.37μM）处理AGS和MKN-45胃癌细胞24小时，Arenobufagin显著增加Cisplatin的效应，抑制细胞活力、迁移和克隆形成，并诱导G2/M期阻滞和凋亡。Arenobufagin通过下调CA9、上调IKBKB和NF-κB/p65激活碱死亡通路，伴随MMP-2/MMP-9表达降低和E-钙黏蛋白表达升高[6]。
在体内，Arenobufagin（3.2mg/kg/day和6.4mg/kg/day）腹腔注射处理荷瘤（SW1990细胞）裸鼠（从接种细胞后第7天开始，隔日一次，持续24天），Arenobufagin显著抑制肿瘤生长，降低肿瘤体积和重量，并诱导肿瘤组织中凋亡和自噬相关蛋白的表达变化[7]。Arenobufagin（0.5mg/kg/day、1mg/k/day和2mg/kg/day）腹腔注射处理荷瘤（HCT116细胞）NOD/SCID小鼠（从尾静脉接种细胞后第1天开始，每日一次，持续32天），Arenobufagin显著减少肺转移结节数量，抑制结直肠癌肺转移[8]。