Bahrami Farnaz, Mekkawy Ahmed H, Badar Samina, Morris David L, Pourgholami Mohammad H
Department of Surgery, Cancer Research Laboratory, University of New South Wales, St George Hospital Sydney Australia.
Department of Medical Physiology, Faculty of Medical Sciences, Tarbiat Modares University Tehran, Iran.
Am J Cancer Res. 2021 Jun 15;11(6):3098-3110. eCollection 2021.
In women, epithelial ovarian cancer is the leading cause of gynaecological malignancy-related deaths. Development of resistance to standard platinum and taxane based chemotherapy and recurrence of the disease necessitate development of novel drugs to halt disease progression. An established concept is to target molecular and signaling pathways that substantially contribute to development of drug resistance and disease progression. We have previously shown that, monepantel (MPL) a novel small molecule acetonitrile derivative is highly effective in suppressing growth, proliferation and colony formation of ovarian cancer cells. These effects are achieved through inhibition of the mTOR/p70S6K pathway in cancer cells. The present study was conducted to find in vivo corroboration and explore the effect of MPL om other growth stimulating putative signaling pathways. Here, female nude mice with subcutaneous OVCAR-3 xenografts were treated with 25 and 50 mg/kg doses of MPL administered (IP) three times weekly for 2 weeks. At the doses employed, MPL was modestly effective at suppressing tumor growth, but highly effective in inhibiting, mTOR, P70S6K and 4EBP1. There were also modest reductions in tumor cyclin D1 and retinoblastoma protein expression. Furthermore, it was found that MPL treatment causes down-regulation of IGF-1R, and c-MYC thus unveiling new dimensions to the growing antitumor actions of this potential anticancer drug. MPL treatment led to reduced tumor volume and weights without causing any detectable side effects. Coupled with the recent human safety data published on this molecule, expanded future trials are highly anticipated.
在女性中，上皮性卵巢癌是妇科恶性肿瘤相关死亡的主要原因。对基于铂和紫杉烷的标准化疗产生耐药性以及疾病复发，使得有必要开发新型药物来阻止疾病进展。一个既定的概念是靶向那些对耐药性发展和疾病进展有重大贡献的分子和信号通路。我们之前已经表明，莫能菌素（MPL）一种新型小分子乙腈衍生物在抑制卵巢癌细胞的生长、增殖和集落形成方面非常有效。这些作用是通过抑制癌细胞中的mTOR/p70S6K通路实现的。本研究旨在进行体内验证，并探索MPL对其他生长刺激假定信号通路的影响。在此，将皮下接种OVCAR-3异种移植物的雌性裸鼠，每周腹腔注射3次，剂量为25和50mg/kg的MPL，持续2周。在所使用的剂量下，MPL在抑制肿瘤生长方面有一定效果，但在抑制mTOR、P70S6K和4EBP1方面非常有效。肿瘤细胞周期蛋白D1和视网膜母细胞瘤蛋白表达也有适度降低。此外，发现MPL治疗导致IGF-1R和c-MYC下调，从而揭示了这种潜在抗癌药物不断增加的抗肿瘤作用的新层面。MPL治疗导致肿瘤体积和重量减小，且未引起任何可检测到的副作用。结合最近发表的关于该分子的人体安全性数据，人们对扩大未来试验寄予厚望。
