title: Reversal of Imatinib resistance in BCR-ABL-positive leukemia after inhibition of the Na+/H+ exchanger.
abstract: The present study was undertaken to estimate the therapeutic benefit to down-regulate the Na(+)/H(+) exchanger 1 (NHE1) for reversing chemoresistance of BCR-ABL-positive leukemia patient cells and cell lines. As a result, after treatment with specific NHE1 inhibitor Cariporide or high K(+) buffer to decrease intracellular pH (pH(i)), cells from relapsed patients exhibited decreased Pgp level, enhanced Rhodamine123 and drug accumulation, decreased colony-forming ability and the modulations of mitogen-activated protein kinases (MAPKs) activities. Furthermore, we used BCR-ABL-positive cell line K562 and its resistant counterparts K562/DOX and K562/G01 cell lines for further study. Together, these findings suggest that Pgp may be associated with the reversal of drug resistance in BCR-ABL-positive leukemia patients and cell lines by the inhibition of NHE1 though MAPK pathways.
authors.affiliation: State Key Laboratory of Experimental Hematology, Institute of Hematology, Hospital of Blood Diseases, Chinese Academy of Medical Sciences, Peking Union Medical College, Tianjin, China.
authors.forename: Weina
authors.initials: W
authors.lastname: Jin
authors.forename: Qinghua
authors.initials: Q
authors.lastname: Li
authors.forename: Yani
authors.initials: Y
authors.lastname: Lin
authors.forename: Ying
authors.initials: Y
authors.lastname: Lu
authors.forename: Huawen
authors.initials: H
authors.lastname: Li
authors.forename: Lihong
authors.initials: L
authors.lastname: Wang
authors.forename: Ronghua
authors.initials: R
authors.lastname: Hu
authors.forename: Li
authors.initials: L
authors.lastname: Ma
authors.forename: Jianxiang
authors.initials: J
authors.lastname: Wang
authors.forename: Tianxiang
authors.initials: T
authors.lastname: Pang
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D001549:Benzamides; D045744:Cell Line, Tumor; D002648:Child; D002675:Child, Preschool; D004317:Doxorubicin / Q000494:pharmacology; D019008:Drug Resistance, Neoplasm; D004357:Drug Synergism; D005260:Female; D006146:Guanidines / Q000494:pharmacology; D006801:Humans; D000068877:Imatinib Mesylate; D020014:K562 Cells; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy* / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D010879:Piperazines / Q000494:pharmacology*; D011743:Pyrimidines / Q000494:pharmacology*; D017923:Sodium-Hydrogen Exchangers / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013450:Sulfones / Q000494:pharmacology; D055815:Young Adult
chemical_list: D001549:Benzamides; D006146:Guanidines; D010879:Piperazines; D011743:Pyrimidines; D017923:Sodium-Hydrogen Exchangers; D013450:Sulfones; C093373:cariporide; D004317:Doxorubicin; D000068877:Imatinib Mesylate; D020928:Mitogen-Activated Protein Kinases