title: The role of paclitaxel in the development and treatment of multidrug resistant cancer cell lines.
abstract: Paclitaxel (PTX) is used for treatment of wide range of solid tumors, but its efficacy is often limited by appearance of multidrug resistance (MDR). We explored the MDR induced by PTX in human colon cancer DLD1 and glioblastoma U87 cell lines. After confirmation of the cross-resistance to other anticancer agents in newly established DLD1-TxR and U87-TxR, we analyzed the mRNA expression of membrane transporters involved in MDR. The cells had increased levels of mdr1 gene expression, while mrp1 was decreased. Flow cytometry analyzes showed that the accumulation of P-glycoprotein (P-gp) substrates (rhodamine 123 and doxorubicin) was significantly lower in DLD1-TxR and U87-TxR compared to DLD1 and U87, respectively. The significant depletion of gst-π gene expression and glutathione (GSH) concentration was observed in U87-TxR. The analysis of cell cycle kinetics revealed extensive cell death in colon cancer cells that were accumulated in subG0 phase after PTX treatment, while glioblastoma cells died during interphase (G1, S or G2). The secretion of vascular endothelial growth factor (VEGF) was inhibited by single PTX treatment of colon cancer and in continuous treatment of glioblastoma cell lines. In conclusion, continuous PTX treatment caused the over-expression of P-gp and acquisition of MDR in colon cancer and glioblastoma cell lines, while some mechanisms of MDR and tumor progression such as GSH detoxification system and VEGF secretion were suppressed. Hence, the present results implicate that PTX is an important clinical tool for colon cancer and glioblastoma treatment even in the presence of MDR.
authors.affiliation: Institute for Biological Research, Department of Neurobiology, University of Belgrade, Bulevar Despota Stefana 142, 11060 Belgrade, Serbia.
authors.forename: Ana
authors.initials: A
authors.lastname: Podolski-Renić
authors.forename: Tijana
authors.initials: T
authors.lastname: Andelković
authors.forename: Jasna
authors.initials: J
authors.lastname: Banković
authors.forename: Nikola
authors.initials: N
authors.lastname: Tanić
authors.forename: Sabera
authors.initials: S
authors.lastname: Ruždijić
authors.forename: Milica
authors.initials: M
authors.lastname: Pešić
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000235:genetics / Q000378:metabolism; D002453:Cell Cycle / Q000187:drug effects; D016923:Cell Death / Q000187:drug effects; D045744:Cell Line, Tumor; D003110:Colonic Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D018450:Disease Progression; D004317:Doxorubicin / Q000493:pharmacokinetics / Q000494:pharmacology; D018432:Drug Resistance, Multiple; D019008:Drug Resistance, Neoplasm; D005909:Glioblastoma / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D005978:Glutathione / Q000378:metabolism; D006801:Humans; D008658:Inactivation, Metabolic; D017239:Paclitaxel / Q000494:pharmacology*; D012333:RNA, Messenger / Q000235:genetics; D020112:Rhodamine 123 / Q000493:pharmacokinetics / Q000494:pharmacology; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
chemical_list: C513055:ABCB1 protein, human; D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D012333:RNA, Messenger; D042461:Vascular Endothelial Growth Factor A; D020112:Rhodamine 123; D004317:Doxorubicin; D005978:Glutathione; D017239:Paclitaxel