title: Reactive Oxygen Species Mediates the Synergistic Activity of Fenretinide Combined with the Microtubule Inhibitor ABT-751 against Multidrug-Resistant Recurrent Neuroblastoma Xenografts.
abstract: ABT-751 is a colchicine-binding site microtubule inhibitor. Fenretinide (4-HPR) is a synthetic retinoid. Both agents have shown activity against neuroblastoma in laboratory models and clinical trials. We investigated the antitumor activity of 4-HPR + the microtubule-targeting agents ABT-751, vincristine, paclitaxel, vinorelbine, or colchicine in laboratory models of recurrent neuroblastoma. Drug cytotoxicity was assessed in vitro by a fluorescence-based assay (DIMSCAN) and in subcutaneous xenografts in nu/nu mice. Reactive oxygen species levels (ROS), apoptosis, and mitochondrial depolarization were measured by flow cytometry; cytochrome c release and proapoptotic proteins were measured by immunoblotting. 4-HPR + ABT-751 showed modest additive or synergistic cytotoxicity, mitochondrial membrane depolarization, cytochrome c release, and caspase activation compared with single agents in vitro; synergism was inhibited by antioxidants (ascorbic acid, α-tocopherol). 4-HPR + ABT-751 was highly active against four xenograft models, achieving multiple maintained complete responses. The median event-free survival (days) for xenografts from 4 patients combined was control = 28, 4-HPR = 49, ABT-751 = 77, and 4-HPR + ABT-751 > 150 (P < 0.001). Apoptosis (terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling, TUNEL) was significantly higher in 4-HPR + ABT-751-treated tumors than with single agents (P < 0.01) and was inhibited by ascorbic acid and α-tocopherol (P < 0.01), indicating that ROS from 4-HPR enhanced the activity of ABT-751. 4-HPR also enhanced the activity against neuroblastoma xenografts of vincristine or paclitaxel, but the latter combinations were less active than 4-HPR + ABT-751. Our data support clinical evaluation of 4-HPR combined with ABT-751 in recurrent and refractory neuroblastoma. Mol Cancer Ther; 15(11); 2653-64. ©2016 AACR.
authors.affiliation: Department of Systems, Biology, and Disease, University of Southern California School of Medicine, Los Angeles, California.
authors.forename: Nancy E
authors.initials: NE
authors.lastname: Chen
authors.affiliation: Department of Pediatrics, Children's Hospital Los Angeles, Los Angeles, California.
authors.forename: N Vanessa
authors.initials: NV
authors.lastname: Maldonado
authors.affiliation: Department of Pediatrics, Children's Hospital Los Angeles, Los Angeles, California.
authors.forename: Vazgen
authors.initials: V
authors.lastname: Khankaldyyan
authors.affiliation: Department of Pathology, Children's Hospital Los Angeles, Los Angeles, California.
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Shimada
authors.affiliation: Cancer Center and Department of Cell Biology and Biochemistry, Pediatrics and Internal Medicine, Texas Tech University Health Sciences Center School of Medicine, Lubbock, Texas.
authors.forename: Michael M
authors.initials: MM
authors.lastname: Song
authors.affiliation: Cancer Center and Department of Cell Biology and Biochemistry, Pediatrics and Internal Medicine, Texas Tech University Health Sciences Center School of Medicine, Lubbock, Texas.
authors.forename: Barry J
authors.initials: BJ
authors.lastname: Maurer
authors.affiliation: Cancer Center and Department of Cell Biology and Biochemistry, Pediatrics and Internal Medicine, Texas Tech University Health Sciences Center School of Medicine, Lubbock, Texas. patrick.reynolds@ttuhsc.edu.
authors.forename: C Patrick
authors.initials: CP
authors.lastname: Reynolds
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D000975:Antioxidants / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D020169:Caspases / Q000378:metabolism; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D045304:Cytochromes c / Q000378:metabolism; D004195:Disease Models, Animal; D018432:Drug Resistance, Multiple; D019008:Drug Resistance, Neoplasm; D017313:Fenretinide / Q000494:pharmacology*; D006801:Humans; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D051379:Mice; D009364:Neoplasm Recurrence, Local; D009447:Neuroblastoma / Q000188:drug therapy / Q000378:metabolism* / Q000401:mortality / Q000473:pathology*; D017382:Reactive Oxygen Species / Q000378:metabolism*; D013449:Sulfonamides / Q000494:pharmacology*; D047368:Tumor Burden / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
chemical_list: C490492:ABT751; D000970:Antineoplastic Agents; D000975:Antioxidants; D017382:Reactive Oxygen Species; D013449:Sulfonamides; D017313:Fenretinide; D045304:Cytochromes c; D020169:Caspases