Circumvention of Mcl-1-dependent drug resistance by simultaneous Chk1 and MEK1/2 inhibition in human multiple myeloma cells

• Published in: PloS one Vol. 9; no. 3; p. e89064
• Main Authors: Pei, Xin-Yan, Dai, Yun, Felthousen, Jessica, Chen, Shuang, Takabatake, Yukie, Zhou, Liang, Youssefian, Leena E, Sanderson, Michael W, Bodie, Wesley W, Kramer, Lora B, Orlowski, Robert Z, Grant, Steven
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 04.03.2014; Public Library of Science (PLoS)
• Subjects: Apoptosis; Apoptosis - drug effects; Apoptosis Regulatory Proteins - metabolism; Bax protein; bcl-2 Homologous Antagonist-Killer Protein - metabolism; bcl-2-Associated X Protein - metabolism; Bcl-2-Like Protein 11; Benzamides - pharmacology; Benzamides - therapeutic use; BIM protein; Biology; Boronic Acids - pharmacology; Bortezomib; Cell culture; Cell Line, Tumor; Cell survival; Checkpoint Kinase 1; CHK1 protein; Cytoprotection - drug effects; Disease resistance; Down-Regulation - drug effects; Drug resistance; Drug Resistance, Neoplasm - drug effects; Gene regulation; Humans; Inhibition; Insulin-like growth factor I; Intercellular Signaling Peptides and Proteins - pharmacology; Interleukin 6; Mcl-1 protein; Medicine; Membrane Proteins - metabolism; Mesenchymal Stem Cells - drug effects; Mesenchymal Stem Cells - metabolism; Mesenchymal Stem Cells - pathology; Mitogen-Activated Protein Kinase Kinases - antagonists & inhibitors; Mitogen-Activated Protein Kinase Kinases - metabolism; Multiple myeloma; Multiple Myeloma - drug therapy; Multiple Myeloma - enzymology; Myeloid Cell Leukemia Sequence 1 Protein - metabolism; Protein Binding - drug effects; Protein Kinase Inhibitors - pharmacology; Protein Kinase Inhibitors - therapeutic use; Protein Kinases - metabolism; Proto-Oncogene Proteins - metabolism; Pyrazines - pharmacology; Stromal cells; Syndecan-1 - metabolism; Transcription; Up-Regulation - drug effects
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0089064

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.