Proteasome inhibitor carfilzomib interacts synergistically with histone deacetylase inhibitor vorinostat in Jurkat T-leukemia cells

• Published in: Acta biochimica et biophysica Sinica Vol. 46; no. 6; pp. 484 - 491
• Main Authors: Gao, Minjie, Gao, Lu, Tao, Yi, Hou, Jun, Yang, Guang, Wu, Xiaosong, Xu, Hongwei, Tompkins, Van S, Han, Ying, Wu, Huiqun, Zhan, Fenghuang, Shi, Jumei
• Format: Journal Article
• Language: English
• Published: China 01.06.2014
• Subjects: Apoptosis - drug effects; Drug Synergism; Histone Deacetylase Inhibitors - pharmacology; Humans; Hydroxamic Acids - pharmacology; Jurkat Cells; Jurkat细胞; Membrane Potential, Mitochondrial - drug effects; Oligopeptides - pharmacology; Proteasome Endopeptidase Complex - drug effects; Reactive Oxygen Species - metabolism; 协同; 去乙酰化; 白血病细胞; 线粒体膜电位; 组蛋白; 蛋白酶体抑制剂; 酶抑制剂; apoptosis; Jurkat; vorinostat; carfilzomib; reactive oxygen species
• ISSN: 1672-9145; 1745-7270
• DOI: 10.1093/abbs/gmu030

In the present study, we investigated the interactions between proteasome inhibitor carfllzomib （CFZ） and histone deacety lase inhibitor vorinostat in Jurkat Tleukemia ceils. Coexposure of cells to minimally lethal concentrations of CFZ with very low concentration of vorinostat resulted in synergistic antiproliferative effects and enhanced apoptosis in Jurkat Tleukemia cells, accompanied with the sharply increased reactive oxygen species （ROS）, the striking de crease in the mitochondrial membrane potential （MMP）, the increased release of cytochrome c, the enhanced activation of caspase9 and 3, and the cleavage of PARP. The com bined treatment of Jurkat cells pretreated with ROS sca vengers Nacetylcysteine （NAC） significantly blocked the loss of mitochondrial membrane potential, suggesting that ROS generation was a former event of the loss of mitochon drial membrane potential. Furthermore, NAC also resulted in a marked reduction in apoptotic cells, indicating a critical role for increased ROS generation by combined treatment. In addition, combined treatment arrested the cell cycle in G2M phase. These results imply that CFZ interacted syner gistically with vorinostat in Jurkat Tleukemia cells, which raised the possibility that the combination of carfflzomib with vorinostat may represent a novel strategy in treating Tcell Leukemia.