The ATM Inhibitor KU60019 Synergizes the Antineoplastic Effect of Romidepsin in Mantle Cell Lymphoma (MCL)

摘要: Introduction: Romidepsin (R), an HDAC inhibitor (HDACi) approved for the treatment of relapsed T-cell lymphoma, is thought to induce cell cycle arrest and apoptosis. Central block proliferation up-regulation cdk p21Cip1/Waf1. Interestingly p21Cip1/Waf1 has also been shown reduce sensitivity romidepsin. inhibitors as a class appear activate expression via ATM. KU60019, specific ATM inhibitor, decrease protein levels in concentration dependent manner. We sought explore potential synergistic interaction with R, given complementary effects around Methods: For all cytotoxicity assays, luminescent viability was performed using CellTiter-GloTM. Gene analysis Western blot semi-quantitative PCR assay. Apoptosis were analyzed Fluorescence-activated sorting (FACS) blot. The efficacy compounds single agent combination evaluated subcutaneous xenograft MCL mouse model. Results: Synergy analyses Jeko-1, Maver-1 Z-138 cells. A cytotoxic effect observed lines when HDACi combined KU60019 throughout range tested concentrations. Flow cytometry three treated agents indicated substantial increase apoptotic fraction R KU60019. Furthermore revealed changes host proteins known be involved control Increased activation programmed death Caspase 8 3 upon combinations lines, resulting increased cleavage Poly (ADP-ribose) polymerase (PARP-1) accumulation DNA damage marker gammaH2AX. Finally, abundance anti-apoptotic Bcl-XL BCL-2 showed significant after plus concentrations compared their presence agents. kill tumor cells by driving premature exit from aberrant mitosis inducing rapid onset p21 addition responsible G2/M phase, not suggesting that apoptosis due ability affect HDACi. Indeed expession Jeko-1 confirmed results inhibition induced arrest. transfection promoter constructs p21(WAF1/Cip1) transcription occurs through Sp1 sites affected at transcriptional level. decreased level SP1 would suggest modulating SP1. survey other types derived (CTCL, DLBCL, TALL ATLL) overall similar one MCL. therapeutic currently model lymphoma line. Conclusions: These data support novel concept dual targeting may effective strategy Disclosures Amengual:Acetylon Pharmaceuticals, INC: Consultancy, Research Funding. Deng:TG Therapeutics, Inc.: Honoraria, Funding; Seattle Genetics: O9Connor:Celgene: Membership on entity9s Board Directors or advisory committees, Acetylon: Other: Consultancy fee; Spectrum Pharmaceuticals: Bristol-Myers Squibb Company: Novartis: Takeda Millenium: fee, Bayer: Honoraria; Mundipharma: