title: 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.affiliation: Department of Hematology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, China.
authors.forename: Minjie
authors.initials: M
authors.lastname: Gao
authors.affiliation: Department of Hematology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, China.
authors.forename: Gege
authors.initials: G
authors.lastname: Chen
authors.affiliation: Department of Hematology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, China.
authors.forename: Houcai
authors.initials: H
authors.lastname: Wang
authors.affiliation: Department of Hematology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, China.
authors.forename: Bingqian
authors.initials: B
authors.lastname: Xie
authors.affiliation: Department of Hematology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, China.
authors.forename: Liangning
authors.initials: L
authors.lastname: Hu
authors.affiliation: Department of Hematology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, China.
authors.forename: Yuanyuan
authors.initials: Y
authors.lastname: Kong
authors.affiliation: Department of Hematology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, China.
authors.forename: Guang
authors.initials: G
authors.lastname: Yang
authors.affiliation: Department of Hematology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, China.
authors.forename: Yi
authors.initials: Y
authors.lastname: Tao
authors.affiliation: Department of Hematology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, China.
authors.forename: Ying
authors.initials: Y
authors.lastname: Han
authors.affiliation: Department of Hematology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, China.
authors.forename: Xiaosong
authors.initials: X
authors.lastname: Wu
authors.affiliation: Department of Hematology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, China.
authors.forename: Yiwen
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Department of Hematology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, China.|College of Life Science and Technology, Tongji University, Shanghai, China.
authors.forename: Bojie
authors.initials: B
authors.lastname: Dai
authors.affiliation: Department of Hematology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, China.
authors.forename: Jumei
authors.initials: J
authors.lastname: Shi
mesh_terms: D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D059447:Cell Cycle Checkpoints / Q000187:drug effects; D045744:Cell Line, Tumor; D006801:Humans; D006877:Hydroxamic Acids / Q000008:administration & dosage; D015459:Leukemia-Lymphoma, Adult T-Cell / Q000473:pathology*; D051379:Mice; D008819:Mice, Nude; D009842:Oligopeptides / Q000008:administration & dosage; D000077337:Vorinostat; D023041:Xenograft Model Antitumor Assays
chemical_list: D006877:Hydroxamic Acids; D009842:Oligopeptides; D000077337:Vorinostat; C524865:carfilzomib
keywords: T-cell leukemia and lymphoma; carfilzomib; vorinostat