title: DNA methyltransferase inhibitor CDA-2 synergizes with high-dose thiotepa and paclitaxel in killing breast cancer stem cells.
abstract: It has been suggested that breast cancer stem cells (CSCs), which characterized by CD44(+)CD24(-/low), may result in treatment failure in patients with breast cancer. It is possible therefore that that inhibiting such subpopulation might subsequently improve clinical outcome. In the present study, we found that the CD44(+)/CD24(-/low) CSCs, isolated from both human breast cell line MCF-7 and MDA-MB-231, were more resistant to thiotepa, paclitaxel and anthracycline, when compared with the non-breast cancer stem cell subset from the same cell lines, whereas the chemosensitivities were remarkably reversed by higher concentration of thiotepa and paclitaxel except for adriamycin. The percentage of CSCs was significantly decreased with an addition of DNA methyltransferase inhibitor CDA-2 and the expression of Smo, Shh, and Gli-1 of Hedgehog signaling pathway in CSCs was decreased. Of important findings, combination of thiotepa or paclitaxel with CDA-2 could significantly inhibit the proliferation of CSCs regardless of their dosages. These results unveiled that the selection of cytotoxic agents and increasing their dosage might be of great importance in the respect of eliminating CSCs. DNA methyltransferase inhibitor CDA-2 exhibited a synergistic effect with cytotoxic drugs, which might provide a conceptually new therapeutic strategy.
authors.affiliation: Department of Medical Oncology, Key laboratory of Carcinogenesis and Translational Research (Ministry of Education, China), Peking University School of Oncology, Beijing Cancer Hospital and Institute, Beijing, China.
authors.forename: Zhihao
authors.initials: Z
authors.lastname: Lu
authors.forename: Jun
authors.initials: J
authors.lastname: Jia
authors.forename: Lijun
authors.initials: L
authors.lastname: Di
authors.forename: Guohong
authors.initials: G
authors.lastname: Song
authors.forename: Yanhua
authors.initials: Y
authors.lastname: Yuan
authors.forename: Bo
authors.initials: B
authors.lastname: Ma
authors.forename: Jing
authors.initials: J
authors.lastname: Yu
authors.forename: Yulin
authors.initials: Y
authors.lastname: Zhu
authors.forename: Xiaoli
authors.initials: X
authors.lastname: Wang
authors.forename: Xinna
authors.initials: X
authors.lastname: Zhou
authors.forename: Jun
authors.initials: J
authors.lastname: Ren
mesh_terms: D001943:Breast Neoplasms / Q000188:drug therapy*; D051927:CD24 Antigen / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D015254:DNA Modification Methylases / Q000037:antagonists & inhibitors*; D017931:DNA Primers / Q000235:genetics; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D005260:Female; D005434:Flow Cytometry; D053823:Hedgehog Proteins / Q000378:metabolism; D006801:Humans; D018960:Hyaluronan Receptors / Q000378:metabolism; D014411:Neoplastic Stem Cells / Q000187:drug effects*; D017239:Paclitaxel / Q000378:metabolism / Q000494:pharmacology*; D010455:Peptides / Q000378:metabolism / Q000494:pharmacology*; D010648:Phenylacetates / Q000378:metabolism / Q000494:pharmacology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000187:drug effects; D013852:Thiotepa / Q000378:metabolism / Q000494:pharmacology*
chemical_list: D051927:CD24 Antigen; D017931:DNA Primers; D053823:Hedgehog Proteins; D018960:Hyaluronan Receptors; D010455:Peptides; D010648:Phenylacetates; C480340:cell differentiation agent II; D013852:Thiotepa; D015254:DNA Modification Methylases; D017239:Paclitaxel