Medina Paul Mark, Ponce Jozelle Marie, Cruz Christian Alfredo
Biological Models Laboratory, Department of Biochemistry and Molecular Biology, College of Medicine, University of the Philippines Manila, Manila, Metro Manila 1000, Philippines.
Biological Models Laboratory, Department of Biochemistry and Molecular Biology, College of Medicine, University of the Philippines Manila, Manila, Metro Manila 1000, Philippines.
Transl Oncol. 2021 Jan;14(1):100940. doi: 10.1016/j.tranon.2020.100940. Epub 2020 Nov 19.
Drug repurposing is used as a strategy for finding new drugs for cancer. The process is a faster and a more cost-effective way of providing new indications for drugs that can address emerging drug resistance and numerous side effects of chemotherapeutic drugs. In this study, the in vivo anticancer potential of itraconazole, disulfiram, etodolac, and ouabain were assessed using five different C. elegans mutant strains. Each strain contains mutations in genes involved in different signaling pathways such as Wnt (JK3476), Notch (JK1107 and BS3164), and Ras-ERK (SD939 and MT2124) that result to phenotypes of sterility, infertility, and multivulva formation. These same signaling pathways have been shown to be defective in several human cancer types. The four candidate drugs were tested on the C. elegans mutant strains to determine if they rescue the mutant phenotypes. Both ouabain and etodolac significantly reduced the sterile and infertile phenotypes of JK3476, JK1107, BS3164, and SD939 strains (p=0.0010). Finally, itraconazole and etodolac significantly reduced multivulva formation (p=0.0021). The degrees of significant phenotypic rescues of each mutant were significantly higher than vehicle only (1% DMSO). Therefore, this study demonstrated that the four candidate drugs have anticancer potential in vivo, and etodolac had the highest anticancer potential.
药物重新利用被用作寻找癌症新药的一种策略。该过程是一种更快且更具成本效益的方式，可为那些能够应对新出现的耐药性以及化疗药物众多副作用的药物提供新的适应症。在本研究中，使用五种不同的秀丽隐杆线虫突变株评估了伊曲康唑、双硫仑、依托度酸和哇巴因的体内抗癌潜力。每个菌株在参与不同信号通路的基因中存在突变，如Wnt（JK3476）、Notch（JK1107和BS3164）以及Ras - ERK（SD939和MT2124），这些突变导致不育、不孕和多阴门形成的表型。已表明这些相同的信号通路在几种人类癌症类型中存在缺陷。在秀丽隐杆线虫突变株上测试了这四种候选药物，以确定它们是否能挽救突变表型。哇巴因和依托度酸均显著降低了JK3476、JK1107、BS3164和SD939菌株的不育和不孕表型（p = 0.0010）。最后，伊曲康唑和依托度酸显著减少了多阴门形成（p = 0.0021）。每个突变体的显著表型挽救程度均显著高于仅使用溶剂（1%二甲基亚砜）的情况。因此，本研究表明这四种候选药物在体内具有抗癌潜力，且依托度酸具有最高的抗癌潜力。
