Carcinogenesis, Vol 18, 943-948, Copyright © 1997 by Oxford University Press
D Delia, A Aiello, L Meroni, M Nicolini, JC Reed and MA Pierotti
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 microM 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 microM 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 microM N-(4-methoxyphenyl) retinamide
(MPR), the structurally similar but biologically inert analog of HPR, nor 3
microM 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.
ARTICLES
Role of antioxidants and intracellular free radicals in retinamide- induced cell death
Istituto Nazionale Tumori, Division of Experimental Oncology A, Milan, Italy.
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