Preclinical ReportsVorinostat and fenretinide synergize in preclinical models of T-cell lymphoid malignanciesMakena, Monish Rama; Nguyen, Thinh H.a,,b; Koneru, Balakrishnaa; Hindle, Ashlya; Chen, Wan-Hsia; Verlekar, Dattesh U.a; Kang, Min H.a,,b,,c; Reynolds, C. Patricka,,b,,c,,d Author Information aCancer Center bPharmacology and Neuroscience cPediatrics dInternal Medicine, Texas Tech University Health Sciences Center School of Medicine, Lubbock, Texas, USA Received 2 July 2020 Revised form accepted 18 September 2020 Supplemental Digital Content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal’s website, www.anti-cancerdrugs.com. Correspondence to C. Patrick Reynolds, MD, PhD, Texas Tech University Health Sciences Center School of Medicine, 3601 4th Street, Stop 9445, Lubbock, TX 79430, USA, Tel: +806 743 1558; fax: +806 743 2990; e-mail: [email protected] Anti-Cancer Drugs 32(1):p 34-43, January 2021. | DOI: 10.1097/CAD.0000000000001008 Buy SDC Metrics Abstract T-cell lymphoid malignancies (TCLMs) are in need of novel and more effective therapies. The histone deacetylase (HDAC) inhibitors and the synthetic cytotoxic retinoid fenretinide have achieved durable clinical responses in T-cell lymphomas as single agents, and patients who failed prior HDAC inhibitor treatment have responded to fenretinide. We have previously shown fenretinide synergized with the class I HDAC inhibitor romidepsin in preclinical models of TCLMs. There exist some key differences between HDAC inhibitors. Therefore, we determined if the pan-HDAC inhibitor vorinostat synergizes with fenretinide. We demonstrated cytotoxic synergy between vorinostat and fenretinide in nine TCLM cell lines at clinically achievable concentrations that lacked cytotoxicity for non-malignant cells (fibroblasts and blood mononuclear cells). In vivo, vorinostat + fenretinide + ketoconazole (enhances fenretinide exposures by inhibiting fenretinide metabolism) showed greater activity in subcutaneous TCLM xenograft models than other groups. Fenretinide + vorinostat increased reactive oxygen species (ROS, measured by 2′,7′-dichlorodihydrofluorescein diacetate dye), resulting in increased apoptosis (via transferase dUTP nick end labeling assay) and histone acetylation (by immunoblotting). The synergistic cytotoxicity, apoptosis, and histone acetylation of fenretinide + vorinostat was abrogated by the antioxidant vitamin C. Like romidepsin, vorinostat combined with fenretinide achieved synergistic cytotoxic activity and increased histone acetylation in preclinical models of TCLMs, but not in non-malignant cells. As vorinostat is an oral agent and not a P-glycoprotein substrate it may have advantages in such combination therapy. These data support conducting a clinical trial of vorinostat combined with fenretinide in relapsed and refractory TCLMs. Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.