title: Induction of chemoresistance in HL-60 cells concomitantly causes a resistance to apoptosis and the synthesis of P-glycoprotein.
abstract: The appearance of multidrug-resistant (MDR) proteins or the acquisition of a defective apoptotic programme are major drawbacks in the treatment of cancers since both induce a resistance to classical chemotherapy. However, a link between the two mechanisms has not, as yet, been clearly established. In this study, HL-60 cells cultured in the continual presence of a sub-lethal dose of doxorubicin (dox; HL-60/Dox) were used as a model to study acquired chemoresistance. During the induction of chemoresistance, the appearance of a functional P-glycoprotein (P-gp), in addition to the expression of anti-apoptotic Bcl-2, Bcl-XL and pro-apoptotic Bax proteins was assessed. Parental cells which are sensitive to dox, have no P-gp activity and express Bcl-2 and Bax. After 4 weeks of treatment, a functional P-gp was detected in HL-60/Dox cells. In addition, the synthesis of Bcl-2 appeared to be replaced by Bcl-XL while that of Bax remained unchanged. These cells were also resistant to apoptosis induced by both P-gp and non-P-gp substrates. This inability to induce apoptosis could have resulted from the induction of the expression of the inhibitor of apoptosis protein (XIAP). Our data show that acquired chemoresistance could involve a parallel induction of P-gp and an impairment of the apoptotic pathway.
authors.affiliation: INSERM U419, Nantes, France.
authors.forename: M
authors.initials: M
authors.lastname: Campone
authors.forename: F
authors.initials: F
authors.lastname: Vavasseur
authors.forename: M T
authors.initials: MT
authors.lastname: Le Cabellec
authors.forename: K
authors.initials: K
authors.lastname: Meflah
authors.forename: F M
authors.initials: FM
authors.lastname: Vallette
authors.forename: L
authors.initials: L
authors.lastname: Oliver
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000096:biosynthesis*; D017209:Apoptosis; D053148:Caspase 3; D020169:Caspases / Q000378:metabolism; D003561:Cytarabine / Q000494:pharmacology; D004317:Doxorubicin / Q000494:pharmacology; D018432:Drug Resistance, Multiple; D004789:Enzyme Activation; D005434:Flow Cytometry; D005452:Fluoresceins / Q000494:pharmacology; D018922:HL-60 Cells / Q000187:drug effects*; D006801:Humans; D010447:Peptide Hydrolases / Q000378:metabolism; D010641:Phenotype; D011339:Probenecid / Q000494:pharmacology; D014176:Protein Biosynthesis; D011506:Proteins; D011518:Proto-Oncogene Proteins / Q000096:biosynthesis; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000096:biosynthesis; D020133:Reverse Transcriptase Polymerase Chain Reaction; D051636:X-Linked Inhibitor of Apoptosis Protein; D051028:bcl-2-Associated X Protein; D051020:bcl-X Protein
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; C494826:BAX protein, human; C494811:BCL2L1 protein, human; D005452:Fluoresceins; D011506:Proteins; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D051636:X-Linked Inhibitor of Apoptosis Protein; C496866:XIAP protein, human; D051028:bcl-2-Associated X Protein; D051020:bcl-X Protein; D003561:Cytarabine; D004317:Doxorubicin; D010447:Peptide Hydrolases; C505407:CASP3 protein, human; D053148:Caspase 3; D020169:Caspases; C108711:DEVDase; D011339:Probenecid; C007740:fluorexon