title: Multi-drug-resistant cells enriched from chronic myeloid leukemia cells by Doxorubicin possess tumor-initiating-cell properties.
abstract: Multiple drug resistance (MDR) occurring during chemotherapy is a major obstacle for treatment of cancers using chemotherapeutic drugs; thus, the mechanisms underlying MDR have attracted intensive attention. Many studies have shown that tumor-initiating cells exhibit a chemotherapeutic tolerance characteristic. However, whether the MDR cells possess tumor-initiating cells properties and its underlying mechanisms remain to be fully elucidated. In this study, we utilized a well-established MDR cell line K562/A02 enriched by doxorubicin from K562 cells to determine if the K562/A02 cells possess tumor-initiating properties and investigated its potential molecular mechanisms. We observed that the expressions of Oct4, Sox2, and Nanog, all of which are well-characterized stem cell markers, in K562/A02 cells were elevated in comparison to parental K562 cells; in addition, we found that K562/A02 cells exhibited more potent in vitro and in vivo tumor-initiating properties, as revealed by sphere assay, self-renewal assay, soft agar assay, and animal studies. Furthermore, our data suggest that snail and twist1, two well known transcriptional factors for the epithelial-mesenchymal transition (EMT) program, may be potentially involved in the acquisition of tumor-initiating properties of K562/A02 cells. Thus, our study demonstrates that MDR K562/A02 cells possess tumor-initiating properties, most likely due to the elevated expressions of snail and twist1.
authors.affiliation: Department of Pharmacology, School of Pharmacy, Fudan University, Shanghai 201203, P.R. China.
authors.forename: Hong
authors.initials: H
authors.lastname: Xin
authors.forename: Ying
authors.initials: Y
authors.lastname: Kong
authors.forename: Xiaoxiao
authors.initials: X
authors.lastname: Jiang
authors.forename: Ke
authors.initials: K
authors.lastname: Wang
authors.forename: Xiaoran
authors.initials: X
authors.lastname: Qin
authors.forename: Ze-Hong
authors.initials: ZH
authors.lastname: Miao
authors.forename: Yizhun
authors.initials: Y
authors.lastname: Zhu
authors.forename: Wenfu
authors.initials: W
authors.lastname: Tan
mesh_terms: D000903:Antibiotics, Antineoplastic / Q000494:pharmacology*; D002471:Cell Transformation, Neoplastic / Q000187:drug effects* / Q000235:genetics; D004317:Doxorubicin / Q000494:pharmacology*; D018432:Drug Resistance, Multiple; D019008:Drug Resistance, Neoplasm; D018398:Homeodomain Proteins / Q000378:metabolism; D006801:Humans; D020014:K562 Cells; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000235:genetics / Q000473:pathology*; D000071317:Nanog Homeobox Protein; D014411:Neoplastic Stem Cells / Q000378:metabolism / Q000473:pathology*; D009687:Nuclear Proteins / Q000378:metabolism / Q000502:physiology; D050814:Octamer Transcription Factor-3 / Q000378:metabolism; D055748:SOXB1 Transcription Factors / Q000378:metabolism; D000071250:Snail Family Transcription Factors; D014157:Transcription Factors / Q000378:metabolism / Q000502:physiology; D051879:Twist-Related Protein 1 / Q000378:metabolism / Q000502:physiology
chemical_list: D000903:Antibiotics, Antineoplastic; D018398:Homeodomain Proteins; C486780:NANOG protein, human; D000071317:Nanog Homeobox Protein; D009687:Nuclear Proteins; D050814:Octamer Transcription Factor-3; C494173:POU5F1 protein, human; C527782:SOX2 protein, human; D055748:SOXB1 Transcription Factors; D000071250:Snail Family Transcription Factors; C103173:TWIST1 protein, human; D014157:Transcription Factors; D051879:Twist-Related Protein 1; D004317:Doxorubicin