Monepantel (AAD1566) is an amino-acetonitrile derivative anthelmintic. Monepantel can inhibit the mTOR/p70S6K signaling pathway to induce autophagy[1-2]. Monepantel is applicable for research in gastrointestinal nematode infections, amyotrophic lateral sclerosis, and tumors[3-4].
In vitro, Monepantel (0-25µM) was applied to human ovarian cancer OVCAR-3 cells for 24-72 hours. Monepantel was able to induce autophagy by inhibiting mTOR phosphorylation and interfering with the mTOR/p70S6K signaling pathway[5]. Monepantel (25µM) was also used in various cancer cell lines, including MDA-MB-435, for 24-48 hours. Monepantel induced an endoplasmic reticulum stress response, upregulated the expression of ATF4, CHOP, and BiP proteins, activated the integrated stress response downstream, and leading to cell cycle arrest[6].
In vivo, Monepantel was administered via intraperitoneal injection (25 and 50mg/kg; three times a week; for 2 weeks) to female nude mice bearing subcutaneous OVCAR-3 ovarian cancer xenografts. Monepantel significantly inhibited tumor growth and reduced both tumor volume and weight[7]. In combination therapy, Monepantel, administered via intraperitoneal injection (25 or 50mg/kg; three times a week; for 2 weeks) along with pegylated liposomal doxorubicin (once a week) or gemcitabine (twice a week) to OVCAR-3 xenograft mice, significantly enhanced the inhibitory effect of the chemotherapeutic agents on tumor growth, induced tumor volume reduction, and demonstrated a synergistic inhibitory effect[8].
References:
[1] Food Safety Commission of Japan. Monepantel (Veterinary Medicinal Products). Food Saf (Tokyo). 2020 Mar 27;8(1):4-5.
[2] Mislang A, Mollard R, Tapia Rico G, et al. A preliminary assessment of oral monepantel's tolerability and pharmacokinetics in individuals with treatment-refractory solid tumors. Cancer Chemother Pharmacol. 2020 Nov;86(5):589-594.
[3] Bahrami F, Morris DL, Rufener L, et al. Anticancer properties of novel aminoacetonitrile derivative monepantel (ADD 1566) in pre-clinical models of human ovarian cancer. Am J Cancer Res. 2014 Sep 6;4(5):545-57.
[4] Canton C, Canton L, Lifschitz A, et al. Monepantel pharmaco-therapeutic evaluation in cattle: Pattern of efficacy against multidrug resistant nematodes. Int J Parasitol Drugs Drug Resist. 2021 Apr;15:162-167.
[5] Bahrami F, Pourgholami MH, Mekkawy AH, et al. Monepantel induces autophagy in human ovarian cancer cells through disruption of the mTOR/p70S6K signalling pathway. Am J Cancer Res. 2014 Sep 6;4(5):558-71.
[6] Harris TJ, Liao Y, Shi W, et al. Induction of endoplasmic reticulum stress is associated with the anti-tumor activity of monepantel across cancer types. Cancer Med. 2023 Jun;12(12):13522-13537.
[7] Bahrami F, Mekkawy AH, Badar S, et al. Monepantel antitumor activity is mediated through inhibition of major cell cycle and tumor growth signaling pathways. Am J Cancer Res. 2021 Jun 15;11(6):3098-3110.
[8] Ataie-Kachoie P, Pillai K, Badar S, et al. Monepantel considerably enhances the therapeutic potentials of PEGylated liposomal doxorubicin and gemcitabine in ovarian cancer: in vitro and in vivo studies. Am J Cancer Res. 2018 Oct 1;8(10):2064-2075.
Monepantel (AAD1566)是一种氨基乙腈衍生物类驱虫药，Monepantel可抑制mTOR/p70S6K信号通路诱导自噬[1-2]。Monepantel可用于胃肠道线虫感染、肌萎缩侧索硬化症和肿瘤等相关研究[3-4]。
在体外，Monepantel（0-25µM）处理人类卵巢癌OVCAR-3细胞24-72小时，Monepantel能够通过抑制mTOR磷酸化并干扰mTOR/p70S6K信号通路，从而诱导自噬[5]。Monepantel（25µM）在包括MDA‐MB‐435在内的多种癌症细胞系24-48小时。Monepantel能诱导内质网应激反应，上调ATF4、CHOP和BiP蛋白表达，激活下游的整合应激反应，导致细胞周期停滞[6]。
在体内，Monepantel以腹腔注射（25和50mg/kg；每周三次；持续2周）处理带有OVCAR-3卵巢癌皮下异种移植瘤的雌性裸鼠，Monepantel显著地抑制肿瘤生长，降低肿瘤体积和重量[7]。Monepantel以腹腔注射（25或50mg/kg；每周三次；持续2周）与聚乙二醇化脂质体多柔比星（每周一次）或吉西他滨（每周两次）联合使用处理OVCAR-3异种移植瘤小鼠，Monepantel能显著增强化疗药物对肿瘤生长的抑制效果，并诱导肿瘤体积缩小，且该抑制作用表现为协同效应[8]。