title: Induced cancer stem-like cells as a model for biological screening and discovery of agents targeting phenotypic traits of cancer stem cell.
abstract: Cancer stem cells (CSCs) retain the capacity to propagate themselves through self-renewal and to produce heterogeneous lineages of cancer cells constituting the tumor. Novel drugs that target CSCs can potentially eliminate the tumor initiating cell population therefore resulting in complete cure of the cancer. We recently established a CSC-like model using induced pluripotent stem cell (iPSC) technology to reprogram and partially differentiate human mammary epithelial MCF-10A cells. Using the induced CSC-like (iCSCL) model, we developed a phenotypic drug assay system to identify agents that inhibit the stemness and self-renewal properties of CSCs. The selectivity of the agents was assessed using three distinct assays characterized by cell viability, cellular stemness and tumor sphere formation. Using this approach, we found that withaferin A (WA), an Ayurvedic medicine constituent, was a potent inhibitor of CSC stemness leading to cellular senescence primarily via the induction of p21Cip1 expression. Moreover, WA exhibited strong anti-tumorigenic activity against the iCSCL. These results indicate that our iCSCL model provides an innovative high throughput platform for a simple, easy, and cost-effective method to search for novel CSC-targeting drugs. Furthermore, our current study identified WA as a putative drug candidate for abrogating the stemness and tumor initiating ability of CSCs.
authors.affiliation: Department of Microbiology, Yokohama City University School of Medicine, Yokohama, Japan.
authors.forename: Mayuko
authors.initials: M
authors.lastname: Nishi
authors.affiliation: Department of Reproductive Biology, National Research Institute for Child Health and Development, Tokyo, Japan.
authors.forename: Hidenori
authors.initials: H
authors.lastname: Akutsu
authors.affiliation: Department of Microbiology, Yokohama City University School of Medicine, Yokohama, Japan.
authors.forename: Ayumi
authors.initials: A
authors.lastname: Kudoh
authors.affiliation: Infectious Disease Surveillance Center, National Institute of Infectious Diseases, Tokyo, Japan.
authors.forename: Hirokazu
authors.initials: H
authors.lastname: Kimura
authors.affiliation: Department of Microbiology, National University of Singapore, Singapore.
authors.forename: Naoki
authors.initials: N
authors.lastname: Yamamoto
authors.affiliation: Department of Reproductive Biology, National Research Institute for Child Health and Development, Tokyo, Japan.
authors.forename: Akihiro
authors.initials: A
authors.lastname: Umezawa
authors.affiliation: Cutaneous Biology Research Center, Massachusetts General Hospital and Harvard Medical School, Charlestown, MA, USA.
authors.forename: Sam W
authors.initials: SW
authors.lastname: Lee
authors.affiliation: Department of Microbiology, Yokohama City University School of Medicine, Yokohama, Japan.
authors.forename: Akihide
authors.initials: A
authors.lastname: Ryo
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D002454:Cell Differentiation / Q000187:drug effects; D002460:Cell Line; D019070:Cell Lineage; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002471:Cell Transformation, Neoplastic / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D065150:Cellular Reprogramming; D016922:Cellular Senescence / Q000187:drug effects; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000235:genetics / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D055808:Drug Discovery / Q000379:methods*; D058750:Epithelial-Mesenchymal Transition / Q000187:drug effects; D057166:High-Throughput Screening Assays; D006801:Humans; D057026:Induced Pluripotent Stem Cells / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D058990:Molecular Targeted Therapy; D014411:Neoplastic Stem Cells / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D010641:Phenotype; D015398:Signal Transduction / Q000187:drug effects; D018874:Spheroids, Cellular; D013997:Time Factors; D014162:Transfection; D054358:Withanolides / Q000494:pharmacology*
chemical_list: D000970:Antineoplastic Agents; C493956:CDKN1A protein, human; D050759:Cyclin-Dependent Kinase Inhibitor p21; D054358:Withanolides; C009684:withaferin A