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

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 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.

• Authors: Minjie Gao, Gege Chen, Houcai Wang, Bingqian Xie, Liangning Hu, Yuanyuan Kong, Guang Yang, Yi Tao, Ying Han, Xiaosong Wu, Yiwen Zhang, Bojie Dai, Jumei Shi
• Journal: Oncotarget (Oncotarget) Vol. 7 Issue 20 Pg. 29102-15 (May 17 2016) ISSN: 1949-2553 [Electronic] United States
• PMID: 27074555 (Publication Type: Journal Article)

Chemical References

• Hydroxamic Acids
• Oligopeptides
• Vorinostat
• carfilzomib

Topics

• Animals
• Antineoplastic Combined Chemotherapy Protocols (pharmacology)
• Apoptosis (drug effects)
• Cell Cycle Checkpoints (drug effects)
• Cell Line, Tumor
• Humans
• Hydroxamic Acids (administration & dosage)
• Leukemia-Lymphoma, Adult T-Cell (pathology)
• Mice
• Mice, Nude
• Oligopeptides (administration & dosage)
• Vorinostat
• Xenograft Model Antitumor Assays