title: Identification of drug candidate against prostate cancer from the aspect of somatic cell reprogramming.
abstract: Considering the similarities between the transcriptional programming involved in cancer progression and somatic cell reprogramming, we tried to identify drugs that would be effective against malignant cancers. We used the early transposon Oct4 and Sox2 enhancer (EOS) system to select human prostate cancer (PCA) cells expressing high levels of OCT4. Patients with metastatic castration-resistant PCA that does not respond to treatment with docetaxel have few therapeutic options. The OCT4-expressing PCA cells selected using the EOS system showed increased tumorigenicity and high resistance to docetaxel, both in vitro and in vivo. By using their gene expression data, expression signature-based prediction for compound candidates identified an antiviral drug, ribavirin, as a conversion modulator from drug resistance to sensitivity. Treatment of PCA cells with ribavirin decreased their resistance against treatment with docetaxel. This indicated that ribavirin reversed the gene expression, including that of humoral factors, in the OCT4-expressing PCA cells selected using the EOS system. Thereby, ribavirin increased the efficacy of docetaxel for cancer cells. We propose a novel cell reprogramming approach, named drug efficacy reprogramming, as a new model for identifying candidate antitumor drugs.
authors.affiliation: Department of Urology, The Sakaguchi Laboratory, School of Medicine, Keio University, Tokyo, Japan.
authors.forename: Takeo
authors.initials: T
authors.lastname: Kosaka
authors.forename: Go
authors.initials: G
authors.lastname: Nagamatsu
authors.forename: Shigeru
authors.initials: S
authors.lastname: Saito
authors.forename: Mototsugu
authors.initials: M
authors.lastname: Oya
authors.forename: Toshio
authors.initials: T
authors.lastname: Suda
authors.forename: Katsuhisa
authors.initials: K
authors.lastname: Horimoto
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D045744:Cell Line, Tumor; D065150:Cellular Reprogramming / Q000187:drug effects; D000077143:Docetaxel; D019008:Drug Resistance, Neoplasm; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D008297:Male; D051379:Mice; D008819:Mice, Nude; D050814:Octamer Transcription Factor-3 / Q000235:genetics / Q000378:metabolism; D064129:Prostatic Neoplasms, Castration-Resistant / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D012254:Ribavirin / Q000494:pharmacology; D055748:SOXB1 Transcription Factors / Q000235:genetics / Q000378:metabolism; D043823:Taxoids / Q000494:pharmacology; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D050814:Octamer Transcription Factor-3; C494173:POU5F1 protein, human; C527782:SOX2 protein, human; D055748:SOXB1 Transcription Factors; D043823:Taxoids; D000077143:Docetaxel; D012254:Ribavirin