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Implication of mitochondria-derived reactive oxygen species, cytochrome C and caspase-3 in N-(4-Hydroxyphenyl)retinamide-induced apoptosis in cervical carcinoma cells

Oncogene volume 18, pages 6380–6387 (1999)Cite this article

Abstract

N-(4-Hydroxyphenyl)retinamide (4HPR) is currently used in cancer prevention and therapy trials. It is thought that its effects result from induction of apoptosis. 4HPR-induced apoptosis in human cervical carcinoma C33A cells involves enhanced generation of reactive oxygen species (ROS). In this study we explored the mechanism by which 4HPR increases ROS and induces apoptosis in these cells. 4HPR induced cytochrome c release from mitochondria to cytoplasm, activated caspase-3, and caused a membrane permeability transition (MPT). All these 4HPR's effects, as well as the induction of apoptosis, were inhibited by antioxidants, which decrease ROS. Thenoyltrifluoroacetone, a mitochondrial respiratory chain (MRC) complex II inhibitor, and carbonylcyanide m-chlorophenyl hydrazone, which uncouples electron transfer and ATP synthesis and inhibits ROS generation by MRC, inhibited 4HPR-induced ROS generation very effectively. Rotenone, an MRC complex I inhibitor was less effective and azide, an MRC complex IV inhibitor, exhibited a marginal effect. In contrast, antimycin A, an MRC complex III inhibitor, enhanced 4HPR-induced ROS generation. These findings suggest that 4HPR enhances ROS generation by affecting a target between complex II and complex III, presumably coenzyme Q. This effect is followed by release of cytochrome c, increased caspase-3 activity, induction of MPT and eventual DNA fragmentation and cell death.

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Acknowledgements

This study was supported in part by United States Public Health Service Grant PO1 CA52051 from the National Cancer Institute. We thank Dafna Lotan for her excellent technical assistance. WK Hong is a Clinical Research Professor for the American Cancer Society. R Lotan is an incumbent of the Irving and Nadine Mansfield and Robert David Levitt Cancer Research Chair.

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Authors and Affiliations

  1. Department of Thoracic/Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd., Houston, 77030, Texas, TX, USA

    Seigo Suzuki, Nobuhiko Oridate, Waun K Hong & Reuben Lotan

  2. Research Center for Cardiovascular Diseases, Institute of Molecular Medicine for the Prevention of Human Diseases, The University of Texas-Houston Health Science Center, Houston, 77030, Texas, TX, USA

    Masahiro Higuchi & Rita J Proske

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  1. Seigo Suzuki
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  2. Masahiro Higuchi
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Suzuki, S., Higuchi, M., Proske, R. et al. Implication of mitochondria-derived reactive oxygen species, cytochrome C and caspase-3 in N-(4-Hydroxyphenyl)retinamide-induced apoptosis in cervical carcinoma cells. Oncogene 18, 6380–6387 (1999). https://doi.org/10.1038/sj.onc.1203024

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