Therapeutic potential and functional interaction of carfilzomib and vorinostat in T-cell leukemia/lymphoma

// Minjie Gao 1 , Gege Chen 1 , Houcai Wang 1 , Bingqian Xie 1 , Liangning Hu 1 , Yuanyuan Kong 1 , Guang Yang 1 , Yi Tao 1 , Ying Han 1 , Xiaosong Wu 1 , Yiwen Zhang 1 , Bojie Dai 1, 2 , Jumei Shi 1 1 Department of Hematology, Shanghai Tenth People’s Hospital, Tongji University School of Medicine, Shanghai, China 2 College of Life Science and Technology, Tongji University, Shanghai, China Correspondence to: Jumei Shi, e-mail: shijumei@tongji.edu.cn Bojie Dai, e-mail: bojiedai@gmail.com Keywords: carfilzomib, vorinostat, T-cell leukemia and lymphoma Received: December 02, 2015      Accepted: March 28, 2016      Published: April 09, 2016 ABSTRACT We previously showed that the proteasome inhibitor carfilzomib and the histone deacetylase inhibitor (HDACI) vorinostat cooperated to induce cell apoptosis in one T-cell leukemia cell line in vitro , implying the possibility of the combination treatment of carfilzomib and vorinostat as a potential therapeutic strategy in human T-cell leukemia/lymphoma. Here we report that combination treatment of carfilzomib and vorinostat enhanced cell apoptosis and induced a marked increase in G 2 -M arrest, reactive oxygen species (ROS) generation, and activated the members of mitogen-activated protein kinases (MAPK) family, including the stress-activated kinases JNK, p38MAPK, and ERK1/2. Carfilzomib/vorinostat-mediated apoptosis was blocked by the ROS scavenger N-acetylcysteine (NAC). The JNK inhibitor SP600125 and the p38MAPK inhibitor SB203580 but not the MEK1/2 inhibitor U0126 significantly attenuated carfilzomib/vorinostat-induced apoptosis, suggesting that p38MAPK and JNK activation contribute to carfilzomib and vorinostat-induced apoptosis. This was further confirmed via short hairpin (shRNA) RNA knockdown of p38MAPK and JNK. Interestingly, the ROS scavenger NAC attenuated carfilzomib/vorinostat-mediated activation of p38MAPK and JNK. However, p38MAPK shRNA but not JNK shRNA diminished carfilzomib/vorinostat-mediated ROS generation. In contrast, overexpression of p38MAPK significantly increased carfilzomib/vorinostat-mediated ROS generation, suggesting that an amplification loop exists between ROS and p38MAPK pathway. Combination treatment of carfilzomib and vorinostat enhanced their individual antitumor activity in both a human xenograft model as well as human primary T-cell leukemia/lymphoma cells. These data suggest the potential clinical benefit and underlying molecular mechanism of combining carfilzomib with vorinostat in the treatment of human T-cell leukemia/lymphoma.