title: Osteoblastic differentiation and P-glycoprotein multidrug resistance in a murine osteosarcoma model.
abstract: A recent study of multidrug resistance (MDR) 1 gene transfected osteosarcoma cells found a cause-effect relationship between increased expression of P-glycoprotein (P-gp) and a low aggressive phenotype. However, several experimental and clinical studies have observed contradictory findings in that P-gp expression has been associated with tumour progression. In the present study, we characterized P-gp-positive and P-gp-negative single-cell clones of a murine osteosarcoma, to further investigate the relationship between P-gp expression and changes in cell phenotype. Although these clones were all selected by doxorubicin (DOX) exposure, they were heterogeneous with respect to MDR1 gene expression. The P-gp-positive clones revealed MDR phenotype, whereas the P-gp-negative clones showed no resistance to drugs. Morphological and functional analysis showed that both the P-gp-positive and P-gp-negative clones were more differentiated than the parent cells in terms of enhanced activity of cellular alkaline phosphatase, an increase in well-organized actin stress fibres and enhanced osteogenic activity. Moreover, these subclones all displayed a decrease in malignant potential such as oncogenic activity, tumour growth rate and metastatic ability, regardless of their P-gp status. These results indicate that the observed osteoblastic differentiation and less aggressive phenotype in DOX-selected osteosarcoma cells may not only be explained by the direct effect of P-gp, and accordingly, consideration of the effect of DOX, as well as P-gp, appears to be important.
authors.affiliation: Department of Orthopaedic Surgery, Kyoto Prefectural University of Medicine, Japan.
authors.forename: H
authors.initials: H
authors.lastname: Takeshita
authors.forename: K
authors.initials: K
authors.lastname: Kusuzaki
authors.forename: H
authors.initials: H
authors.lastname: Murata
authors.forename: T
authors.initials: T
authors.lastname: Suginoshita
authors.forename: M
authors.initials: M
authors.lastname: Hirata
authors.forename: S
authors.initials: S
authors.lastname: Hashiguchi
authors.forename: T
authors.initials: T
authors.lastname: Ashihara
authors.forename: M C
authors.initials: MC
authors.lastname: Gebhardt
authors.forename: H J
authors.initials: HJ
authors.lastname: Mankin
authors.forename: Y
authors.initials: Y
authors.lastname: Hirasawa
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000096:biosynthesis* / Q000235:genetics; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D002454:Cell Differentiation; D002471:Cell Transformation, Neoplastic; D004195:Disease Models, Animal; D004317:Doxorubicin / Q000494:pharmacology; D018432:Drug Resistance, Multiple; D051379:Mice; D010006:Osteoblasts / Q000166:cytology*; D012516:Osteosarcoma / Q000473:pathology*; D010641:Phenotype; D014407:Tumor Cells, Cultured
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000970:Antineoplastic Agents; D004317:Doxorubicin