title: Reactive Oxygen Species-Mediated Synergism of Fenretinide and Romidepsin in Preclinical Models of T-cell Lymphoid Malignancies.
abstract: T-cell lymphoid malignancies (TCLM) are in need of novel and more effective therapies. The histone deacetylase (HDAC) inhibitor romidepsin and the synthetic cytotoxic retinoid fenretinide both have achieved durable clinical responses in T-cell lymphomas as single agents. We investigated the potential for using these two agents in combination in TCLMs. We demonstrated cytotoxic synergy between romidepsin and fenretinide in 15 TCLM cell lines at clinically achievable concentrations that lacked cytotoxicity for nonmalignant cells (fibroblasts and blood mononuclear cells).In vivo, romidepsin + fenretinide + ketoconazole (enhances fenretinide exposures by inhibiting fenretinide metabolism) showed greater activity in subcutaneous and disseminated TCLM xenograft models than single-agent romidepsin or fenretinide + ketoconazole. Fenretinide + romidepsin caused a reactive oxygen species (ROS)-dependent increase in proapoptotic proteins (Bim, tBid, Bax, and Bak), apoptosis, and inhibition of HDAC enzymatic activity, which achieved a synergistic increase in histone acetylation. The synergistic cytotoxicity, apoptosis, and histone acetylation of fenretinide + romidepsin were abrogated by antioxidants (vitamins C or E). Romidepsin + fenretinide activated p38 and JNK via ROS, and knockdown of p38 and JNK1 significantly decreased the synergistic cytotoxicity. Romidepsin + fenretinide also showed synergistic cytotoxicity for B-lymphoid malignancy cell lines, but did not increase ROS, acetylation of histones, activation of p38 + JNK, or cytotoxicity in nonmalignant cells. Romidepsin + fenretinide achieved synergistic activity in preclinical models of TCLMs, but not in nonmalignant cells, via a novel molecular mechanism. These data support conducting clinical trials of romidepsin + fenretinide in relapsed and refractory TCLMs.Mol Cancer Ther; 16(4); 649-61. ©2017 AACR.
authors.affiliation: Cancer Center, Texas Tech University Health Sciences Center School of Medicine, Lubbock, Texas.|Department of Cell Biology and Biochemistry, Texas Tech University Health Sciences Center School of Medicine, Lubbock, Texas.
authors.forename: Monish R
authors.initials: MR
authors.lastname: Makena
authors.affiliation: Cancer Center, Texas Tech University Health Sciences Center School of Medicine, Lubbock, Texas.|Department of Cell Biology and Biochemistry, Texas Tech University Health Sciences Center School of Medicine, Lubbock, Texas.
authors.forename: Balakrishna
authors.initials: B
authors.lastname: Koneru
authors.affiliation: Cancer Center, Texas Tech University Health Sciences Center School of Medicine, Lubbock, Texas.|Department of Cell Biology and Biochemistry, Texas Tech University Health Sciences Center School of Medicine, Lubbock, Texas.|Department of Pharmacology and Neuroscience, Texas Tech University Health Sciences Center School of Medicine, Lubbock, Texas.
authors.forename: Thinh H
authors.initials: TH
authors.lastname: Nguyen
authors.affiliation: Cancer Center, Texas Tech University Health Sciences Center School of Medicine, Lubbock, Texas.|Department of Cell Biology and Biochemistry, Texas Tech University Health Sciences Center School of Medicine, Lubbock, Texas.|Department of Pharmacology and Neuroscience, Texas Tech University Health Sciences Center School of Medicine, Lubbock, Texas.
authors.forename: Min H
authors.initials: MH
authors.lastname: Kang
authors.affiliation: Cancer Center, Texas Tech University Health Sciences Center School of Medicine, Lubbock, Texas. patrick.reynolds@ttuhsc.edu.|Department of Cell Biology and Biochemistry, Texas Tech University Health Sciences Center School of Medicine, Lubbock, Texas.|Department of Pharmacology and Neuroscience, Texas Tech University Health Sciences Center School of Medicine, Lubbock, Texas.|Department of Pediatrics, Texas Tech University Health Sciences Center School of Medicine, Lubbock, Texas.|Department of Internal Medicine, Texas Tech University Health Sciences Center School of Medicine, Lubbock, Texas.
authors.forename: C Patrick
authors.initials: CP
authors.lastname: Reynolds
mesh_terms: D000107:Acetylation / Q000187:drug effects; D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage* / Q000494:pharmacology; D051017:Apoptosis Regulatory Proteins / Q000235:genetics; D045744:Cell Line, Tumor; D047630:Depsipeptides / Q000008:administration & dosage* / Q000378:metabolism; D004357:Drug Synergism; D017313:Fenretinide / Q000008:administration & dosage* / Q000494:pharmacology; D015972:Gene Expression Regulation, Neoplastic; D006657:Histones / Q000378:metabolism; D006801:Humans; D015459:Leukemia-Lymphoma, Adult T-Cell / Q000188:drug therapy* / Q000378:metabolism; D051379:Mice; D017382:Reactive Oxygen Species / Q000378:metabolism*; D023041:Xenograft Model Antitumor Assays
chemical_list: D051017:Apoptosis Regulatory Proteins; D047630:Depsipeptides; D006657:Histones; D017382:Reactive Oxygen Species; D017313:Fenretinide; C087123:romidepsin