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Molecular Cancer Therapeutics

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Small Molecule Therapeutics

Reactive Oxygen Species Mediates the Synergistic Activity of Fenretinide Combined with the Microtubule Inhibitor ABT-751 against Multidrug-Resistant Recurrent Neuroblastoma Xenografts

Nancy E. Chen, N. Vanessa Maldonado, Vazgen Khankaldyyan, Hiroyuki Shimada, Michael M. Song, Barry J. Maurer and C. Patrick Reynolds
Nancy E. Chen
Department of Systems, Biology, and Disease, University of Southern California School of Medicine, Los Angeles, California.
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N. Vanessa Maldonado
Department of Pediatrics, Children's Hospital Los Angeles, Los Angeles, California.
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Vazgen Khankaldyyan
Department of Pediatrics, Children's Hospital Los Angeles, Los Angeles, California.
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Hiroyuki Shimada
Department of Pathology, Children's Hospital Los Angeles, Los Angeles, California.
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Michael M. Song
Cancer Center and Department of Cell Biology and Biochemistry, Pediatrics and Internal Medicine, Texas Tech University Health Sciences Center School of Medicine, Lubbock, Texas.
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Barry J. Maurer
Cancer Center and Department of Cell Biology and Biochemistry, Pediatrics and Internal Medicine, Texas Tech University Health Sciences Center School of Medicine, Lubbock, Texas.
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C. Patrick Reynolds
Cancer Center and Department of Cell Biology and Biochemistry, Pediatrics and Internal Medicine, Texas Tech University Health Sciences Center School of Medicine, Lubbock, Texas.
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  • For correspondence: patrick.reynolds@ttuhsc.edu
DOI: 10.1158/1535-7163.MCT-16-0156
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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); 1–12. ©2016 AACR.

Footnotes

  • Note: Supplementary data for this article are available at Molecular Cancer Therapeutics Online (http://mct.aacrjournals.org/).

  • Received March 16, 2016.
  • Revision received July 20, 2016.
  • Accepted August 2, 2016.
  • ©2016 American Association for Cancer Research.
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Published OnlineFirst October 12, 2016
doi: 10.1158/1535-7163.MCT-16-0156

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Reactive Oxygen Species Mediates the Synergistic Activity of Fenretinide Combined with the Microtubule Inhibitor ABT-751 against Multidrug-Resistant Recurrent Neuroblastoma Xenografts
Nancy E. Chen, N. Vanessa Maldonado, Vazgen Khankaldyyan, Hiroyuki Shimada, Michael M. Song, Barry J. Maurer and C. Patrick Reynolds
Mol Cancer Ther October 12 2016 DOI: 10.1158/1535-7163.MCT-16-0156

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Reactive Oxygen Species Mediates the Synergistic Activity of Fenretinide Combined with the Microtubule Inhibitor ABT-751 against Multidrug-Resistant Recurrent Neuroblastoma Xenografts
Nancy E. Chen, N. Vanessa Maldonado, Vazgen Khankaldyyan, Hiroyuki Shimada, Michael M. Song, Barry J. Maurer and C. Patrick Reynolds
Mol Cancer Ther October 12 2016 DOI: 10.1158/1535-7163.MCT-16-0156
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Molecular Cancer Therapeutics
eISSN: 1538-8514
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