Prolonged early G(1) arrest by selective CDK4/CDK6 inhibition sensitizes myeloma cells to cytotoxic killing through cell cycle-coupled loss of IRF4 Journal Article
| Authors: | Huang, X.; Di Liberto, M.; Jayabalan, D.; Liang, J.; Ely, S.; Bretz, J.; Shaffer, A. L. 3rd; Louie, T.; Chen, I.; Randolph, S.; Hahn, W. C.; Staudt, L. M.; Niesvizky, R.; Moore, M. A. S.; Chen-Kiang, S. |
| Article Title: | Prolonged early G(1) arrest by selective CDK4/CDK6 inhibition sensitizes myeloma cells to cytotoxic killing through cell cycle-coupled loss of IRF4 |
| Abstract: | Dysregulation of cyclin-dependent kinase 4 (CDK4) and CDK6 by gain of function or loss of inhibition is common in human cancer, including multiple myeloma, but success in targeting CDK with broad-spectrum inhibitors has been modest. By selective and reversible inhibition of CDK4/CDK6, we have developed a strategy to both inhibit proliferation and enhance cytotoxic killing of cancer cells. We show that induction of prolonged early-G 1 arrest (pG1) by CDK4/CDK6 inhibition halts gene expression in early-G 1 and prevents expression of genes programmed for other cell-cycle phases. Removal of the early-G 1 block leads to S-phase synchronization (pG1-S) but fails to completely restore scheduled gene expression. Consequently, the IRF4 protein required to protect myeloma cells from apoptosis is markedly reduced in pG1 and further in pG1-S in response to cytotoxic agents, such as the proteasome inhibitor bortezomib. The coordinated loss of IRF4 and gain of Bim sensitize myeloma tumor cells to bortezomib-induced apoptosis in pG1 in the absence of Noxa and more profoundly in pG1-S in cooperation with Noxa in vitro. Induction of pG1 and pG1-S by reversible CDK4/CDK6 inhibition further augments tumor-specific bortezomib killing in myeloma xenografts. Reversible inhibition of CDK4/CDK6 in sequential combination therapy thus represents a novel mechanism-based cancer therapy. |
| Keywords: | adult; controlled study; aged; unclassified drug; human cell; nonhuman; drug targeting; mouse; actin; animal tissue; cell cycle s phase; protein bcl 2; unindexed drug; apoptosis; bortezomib; enzyme inhibition; multiple myeloma; gene expression; animal experiment; animal model; bim protein; caspase 3; cytotoxicity; in vitro study; tumor xenograft; protein bcl xl; drug mechanism; protein mcl 1; protein p27; cell cycle arrest; caspase 8; caspase 9; 6 acetyl 8 cyclopentyl 5 methyl 2 [5 (1 piperazinyl) 2 pyridinylamino] 8h pyrido[2,3 d]pyrimidin 7 one; cyclin a; retinoblastoma protein; tubulin; cell protection; nicotinamide adenine dinucleotide adenosine diphosphate ribosyltransferase; cell cycle g1 phase; cell killing; cyclin e; cyclin dependent kinase 4; s phase kinase associated protein 2; puma protein; interferon regulatory factor 4; cyclin dependent kinase 6; cyclin d2; protein bid; cell synchronization; myeloma cell; protein noxa; cyclin e1; alpha tubulin; protein bim el; protein bim l; protein bim s |
| Journal Title: | Blood |
| Volume: | 120 |
| Issue: | 5 |
| ISSN: | 0006-4971 |
| Publisher: | American Society of Hematology |
| Date Published: | 2012-08-02 |
| Start Page: | 1095 |
| End Page: | 1106 |
| Language: | English |
| DOI: | 10.1182/blood-2012-03-415984 |
| PROVIDER: | scopus |
| PMCID: | PMC3412331 |
| PUBMED: | 22718837 |
| DOI/URL: | |
| Notes: | --- - "Export Date: 4 September 2012" - "CODEN: BLOOA" - "Source: Scopus" |
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