Therapeutic potential and functional interaction of carfilzomib and vorinostat in T-cell leukemia/lymphoma
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Minjie Gao1, Gege Chen1, Houcai Wang1, Bingqian Xie1, Liangning Hu1, Yuanyuan Kong1, Guang Yang1, Yi Tao1, Ying Han1, Xiaosong Wu1, Yiwen Zhang1, Bojie Dai1,2, Jumei Shi1
1Department of Hematology, Shanghai Tenth People’s Hospital, Tongji University School of Medicine, Shanghai, China
2College of Life Science and Technology, Tongji University, Shanghai, China
Jumei Shi, e-mail: email@example.com
Bojie Dai, e-mail: firstname.lastname@example.org
Keywords: carfilzomib, vorinostat, T-cell leukemia and lymphoma
Received: December 02, 2015 Accepted: March 28, 2016 Published: April 09, 2016
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 G2-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.
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