title: Circumvention of Mcl-1-dependent drug resistance by simultaneous Chk1 and MEK1/2 inhibition in human multiple myeloma cells.
abstract: The anti-apoptotic protein Mcl-1 plays a major role in multiple myeloma (MM) cell survival as well as bortezomib- and microenvironmental forms of drug resistance in this disease. Consequently, there is a critical need for strategies capable of targeting Mcl-1-dependent drug resistance in MM. The present results indicate that a regimen combining Chk1 with MEK1/2 inhibitors effectively kills cells displaying multiple forms of drug resistance stemming from Mcl-1 up-regulation in association with direct transcriptional Mcl-1 down-regulation and indirect disabling of Mcl-1 anti-apoptotic function through Bim up-regulation and increased Bim/Mcl-1 binding. These actions release Bak from Mcl-1, accompanied by Bak/Bax activation. Analogous events were observed in both drug-naïve and acquired bortezomib-resistant MM cells displaying increased Mcl-1 but diminished Bim expression, or cells ectopically expressing Mcl-1. Moreover, concomitant Chk1 and MEK1/2 inhibition blocked Mcl-1 up-regulation induced by IL-6/IGF-1 or co-culture with stromal cells, effectively overcoming microenvironment-related drug resistance. Finally, this regimen down-regulated Mcl-1 and robustly killed primary CD138+ MM cells, but not normal hematopoietic cells. Together, these findings provide novel evidence that this targeted combination strategy could be effective in the setting of multiple forms of Mcl-1-related drug resistance in MM.
authors.affiliation: Division of Hematology/Oncology, Department of Medicine, Virginia Commonwealth University and the Massey Cancer Center, Richmond, Virginia, United States of America.
authors.forename: Xin-Yan
authors.initials: XY
authors.lastname: Pei
authors.affiliation: Division of Hematology/Oncology, Department of Medicine, Virginia Commonwealth University and the Massey Cancer Center, Richmond, Virginia, United States of America.
authors.forename: Yun
authors.initials: Y
authors.lastname: Dai
authors.affiliation: Division of Hematology/Oncology, Department of Medicine, Virginia Commonwealth University and the Massey Cancer Center, Richmond, Virginia, United States of America.
authors.forename: Jessica
authors.initials: J
authors.lastname: Felthousen
authors.affiliation: Division of Hematology/Oncology, Department of Medicine, Virginia Commonwealth University and the Massey Cancer Center, Richmond, Virginia, United States of America.
authors.forename: Shuang
authors.initials: S
authors.lastname: Chen
authors.affiliation: Division of Hematology/Oncology, Department of Medicine, Virginia Commonwealth University and the Massey Cancer Center, Richmond, Virginia, United States of America.
authors.forename: Yukie
authors.initials: Y
authors.lastname: Takabatake
authors.affiliation: Division of Hematology/Oncology, Department of Medicine, Virginia Commonwealth University and the Massey Cancer Center, Richmond, Virginia, United States of America.
authors.forename: Liang
authors.initials: L
authors.lastname: Zhou
authors.affiliation: Division of Hematology/Oncology, Department of Medicine, Virginia Commonwealth University and the Massey Cancer Center, Richmond, Virginia, United States of America.
authors.forename: Leena E
authors.initials: LE
authors.lastname: Youssefian
authors.affiliation: Division of Hematology/Oncology, Department of Medicine, Virginia Commonwealth University and the Massey Cancer Center, Richmond, Virginia, United States of America.
authors.forename: Michael W
authors.initials: MW
authors.lastname: Sanderson
authors.affiliation: Division of Hematology/Oncology, Department of Medicine, Virginia Commonwealth University and the Massey Cancer Center, Richmond, Virginia, United States of America.
authors.forename: Wesley W
authors.initials: WW
authors.lastname: Bodie
authors.affiliation: Division of Hematology/Oncology, Department of Medicine, Virginia Commonwealth University and the Massey Cancer Center, Richmond, Virginia, United States of America.
authors.forename: Lora B
authors.initials: LB
authors.lastname: Kramer
authors.affiliation: Department of Lymphoma/Myeloma, the University of Texas MD Anderson Cancer Center, Houston, Texas, United States of America.
authors.forename: Robert Z
authors.initials: RZ
authors.lastname: Orlowski
authors.affiliation: Division of Hematology/Oncology, Department of Medicine, Virginia Commonwealth University and the Massey Cancer Center, Richmond, Virginia, United States of America; Department of Biochemistry, Virginia Commonwealth University and the Massey Cancer Center and Institute of Molecular Medicine, Richmond, Virginia, United States of America.
authors.forename: Steven
authors.initials: S
authors.lastname: Grant
mesh_terms: D017209:Apoptosis / Q000187:drug effects; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism; D000072224:Bcl-2-Like Protein 11; D001549:Benzamides / Q000494:pharmacology / Q000627:therapeutic use; D001897:Boronic Acids / Q000494:pharmacology; D000069286:Bortezomib; D045744:Cell Line, Tumor; D000071877:Checkpoint Kinase 1; D019610:Cytoprotection / Q000187:drug effects; D015536:Down-Regulation / Q000187:drug effects; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000494:pharmacology; D008565:Membrane Proteins / Q000378:metabolism; D059630:Mesenchymal Stem Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D020929:Mitogen-Activated Protein Kinase Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D009101:Multiple Myeloma / Q000188:drug therapy* / Q000201:enzymology*; D064549:Myeloid Cell Leukemia Sequence 1 Protein / Q000378:metabolism*; D011485:Protein Binding / Q000187:drug effects; D047428:Protein Kinase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D011494:Protein Kinases / Q000378:metabolism*; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D011719:Pyrazines / Q000494:pharmacology; D053668:Syndecan-1 / Q000378:metabolism; D015854:Up-Regulation / Q000187:drug effects; D050998:bcl-2 Homologous Antagonist-Killer Protein / Q000378:metabolism; D051028:bcl-2-Associated X Protein / Q000378:metabolism
chemical_list: C120227:2-(2-chloro-4-iodophenylamino)-N-cyclopropylmethoxy-3,4-difluorobenzamide; D051017:Apoptosis Regulatory Proteins; C000606775:BCL2L11 protein, human; D000072224:Bcl-2-Like Protein 11; D001549:Benzamides; D001897:Boronic Acids; D036341:Intercellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D047428:Protein Kinase Inhibitors; D011518:Proto-Oncogene Proteins; D011719:Pyrazines; D053668:Syndecan-1; D050998:bcl-2 Homologous Antagonist-Killer Protein; D051028:bcl-2-Associated X Protein; D000069286:Bortezomib; D011494:Protein Kinases; C000605867:CHEK1 protein, human; D000071877:Checkpoint Kinase 1; D020929:Mitogen-Activated Protein Kinase Kinases