title: Characterization of multidrug‑resistant osteosarcoma sublines and the molecular mechanisms of resistance.
abstract: Multidrug resistance (MDR) is a challenge for the treatment of cancer and the underlying molecular mechanisms remain elusive. The current study exposed MG63 osteosarcoma cells to increasing concentrations of vincristine (VCR) to establish four VCR‑resistant MG63/VCR cell sublines (MG63/VCR1, 2, 3 and 4). The drug resistance indices (RI) of these sublines was detected with the CCK‑8 assay and determined to be163, 476, 1,247, and 2,707‑fold higher than that of parental cells, respectively. These sublines also exhibited cross‑resistance to doxorubicin, paclitaxel and pirarubicin. With increased RI, the proliferative capacity of these sublines was gradually reduced and cell morphology was also altered, characterized by increased formation of pseudopodia and long cytoplasmic processes at opposite poles. However, the migration capacity and expression of certain drug resistance‑associated genes were not in accordance with the increased RI; multidrug resistance protein 1 (MDR1) expression was significantly increased in these sublines compared with parental cells. However, in the highly resistant MG63/VCR3 and MG63/VCR4 cells, MDR‑associated protein 1, topoisomerase II and LIM domain kinase 1 levels were significantly reduced compared with the moderately resistant MG63/VCR2 cells. Expression of glutathione S‑transferase‑π mRNA was determined using reverse transcription‑quantitative polymerase chain reaction and determined that it was not changed between MG63 and MG63/VCR cells. The data of the present study demonstrated that the molecular alterations of drug resistance may change with the degree of drug resistance. Taking cell morphology into consideration, the intratumor clonal and phenotypic heterogeneity may be responsible for drug resistance. These MG63/VCR sublines may be a valuable tool to assess drug resistance and the underlying mechanisms, and to identify novel drug resistance‑associated genes or strategies to overcome MDR in human osteosarcoma.
authors: Scientific Research Center, China‑Japan Union Hospital of Jilin University, Changchun, Jilin 130033, P.R. China.
authors: Jian-Zeng
authors: JZ
authors: Yang
authors: Endoscopy Center, China‑Japan Union Hospital of Jilin University, Changchun, Jilin 130033, P.R. China.
authors: Shu-Rong
authors: SR
authors: Ma
authors: Scientific Research Center, China‑Japan Union Hospital of Jilin University, Changchun, Jilin 130033, P.R. China.
authors: Xiao-Li
authors: XL
authors: Rong
authors: Department of Gastroenterology and Hypothyroid Surgery, The Fifth Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450000, P.R. China.
authors: Mei-Ju
authors: MJ
authors: Zhu
authors: Scientific Research Center, China‑Japan Union Hospital of Jilin University, Changchun, Jilin 130033, P.R. China.
authors: Qiu-Ye
authors: QY
authors: Ji
authors: Scientific Research Center, China‑Japan Union Hospital of Jilin University, Changchun, Jilin 130033, P.R. China.
authors: Ling-Jie
authors: LJ
authors: Meng
authors: Scientific Research Center, China‑Japan Union Hospital of Jilin University, Changchun, Jilin 130033, P.R. China.
authors: Yi-Yao
authors: YY
authors: Gao
authors: Scientific Research Center, China‑Japan Union Hospital of Jilin University, Changchun, Jilin 130033, P.R. China.
authors: Yu-Dan
authors: YD
authors: Yang
authors: Scientific Research Center, China‑Japan Union Hospital of Jilin University, Changchun, Jilin 130033, P.R. China.
authors: Yan
authors: Y
authors: Wang
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000235:genetics*; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001859:Bone Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D001842:Bone and Bones / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D018432:Drug Resistance, Multiple; D019008:Drug Resistance, Neoplasm; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D012516:Osteosarcoma / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D014750:Vincristine / Q000494:pharmacology*
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000970:Antineoplastic Agents; D014750:Vincristine