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Revealing the anticancer potential of candidate drugs in vivo using Caenorhabditis elegans mutant strains.

ABSTRACT: 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.

SUBMITTER: Medina PM

PROVIDER: S-EPMC7689339 | biostudies-literature | 2020 Nov

REPOSITORIES: biostudies-literature

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Revealing the anticancer potential of candidate drugs in vivo using Caenorhabditis elegans mutant strains.

Medina Paul Mark PM Ponce Jozelle Marie JM Cruz Christian Alfredo CA

Translational oncology 20201119 1

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 pathwa ...[more]

PMID: 33221682

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Project description:RET/GDNF and ET3/EDNRB regulate cell survival, differentiation and migration of neural crest-derived cells. Many signalling mediators of RET have been characterized but the target genes at the end of the signalling cascade are largely unknown. Since the RET/EDNRB crosstalk has been previously shown, we used a Caenorhabditis elegans knockout strain of Nep-1, a homologue of human ECE1 (endothelin-converting enzyme-1), to identify new target genes. Transcriptome comparison between wild-type and Nep-1 strains at different stages identified vit-3 as a differentially expressed gene. Molecular studies of the vit3 mammalian homologue, Apoliporotein B (APOB), were performed in the murine Neuro2a cell line, a model of ENS development. Apob expression in Neuro2a is specifically activated by the RET/GDNF signalling pathway, since Ret silencing abolished Apob increase, and this effect is induced by MAPK P38 kinase activation. Mouse Apob promoter study revealed that there is a p53-dependent repressor element in the promoter region which blocks Apob expression and we show that actually p53 binds to this region. We demonstrated that RET/GDNF and EDNRB/endothelin 3 (ET-3) cooperate in inducing neuronal differentiation resulting in Apob activation. We also show that Apob expression is downregulated in mouse embryos homozygous for the mutation RetC620R and presenting a severe HSCR phenotype, whereas heterozygous mice, phenotypically normal, present a significant increase in Apob expression. These data suggest that Apob has an important role in RET-mediated neuronal development and APOB decrease may have an impact in human disorders where RET absence has been already identified, such as HSCR and Parkinson disease. Gene expression analysis using Affymetrix GeneChip C. elegans arrays in order to identify genes up- or down-regulated in nep-1 strains, homologue of human ECE1 (endothelin-converting enzyme 1). Comparison of the transcriptomes between wt and nep-1 strains in larval stage L3 and adult C. elegans.

Dataset Information

Revealing the anticancer potential of candidate drugs in vivo using Caenorhabditis elegans mutant strains.

Publications

Revealing the anticancer potential of candidate drugs in vivo using Caenorhabditis elegans mutant strains.

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