Role of antioxidants and intracellular free radicals in retinamide-induced cell death

Domenico Delia, Antonella Aiello, Luca Meroni, Marco Nicolini, John C. Reed, Marco A. Pierotti

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Abstract

The cancer chemopreventive synthetic retinoid N-(4-hydroxyphenyl)retinamide (HPR) possesses antiproliferative and apoptotic activity at pharmacological doses. In this study we show that addition of antioxidants to HL-60 cells cultured in the presence of 3 μM HPR, markedly suppresses the apoptopic effect of the retinoid and significantly prolongs cell survival (48-96 h). We also show, by the use of the oxidation-sensitive probe 2',7'-dichlorofluorescin diacetate (DCF-DA) and in combination with flow cytometric and spectrofluorimetric analysis, that treatment of cells with 3 μM HPR results in an immediate and sustained production of intracellular free radicals, most likely hydroperoxides. Interestingly, the formation of these HPR-induced free radicals is effectively blocked by the water soluble antioxidants L-ascorbic acid and N-acetyl-L-cysteine. Neither 3-15 μM N-(4-methoxyphenyl) retinamide (MPR), the structurally similar but biologically inert analog of HPR, nor 3 μM doses of the retinoids all-trans retinoic acid, 9-cis-retinoic acid, TTNPB and SR11237 induce intracellular free radicals, thus indicating that the specificity of this phenomenon is restricted to HPR. Altogether, we provide the first direct evidence that HPR stimulates the generation of intracellular free radicals, which appear to have a causative role in the induction of apoptosis in vitro. Our findings raise the possibility that the therapeutic efficacy of HPR may, at least in part, depend on these apoptosis-inducing oxidative phenomena.

Original languageEnglish
Pages (from-to)943-948
Number of pages6
JournalCarcinogenesis
Volume18
Issue number5
DOIs
Publication statusPublished - May 1997

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ASJC Scopus subject areas

  • Cancer Research

Cite this

Delia, D., Aiello, A., Meroni, L., Nicolini, M., Reed, J. C., & Pierotti, M. A. (1997). Role of antioxidants and intracellular free radicals in retinamide-induced cell death. Carcinogenesis, 18(5), 943-948. https://doi.org/10.1093/carcin/18.5.943