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Dopamine agonists and analogues have an antiproliferative effect on CHO-K1 cells

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Abstract

Epidemiological studies have shown a reduced incidence of cancer in Parkinson’s disease. Since nearly all parkinsonian patients with clinical impairment are treated with L-β-3,4-dihydroxyphenylalanine (L-DOPA) and dopamine (DA)ergic agonists, a possibility exists that these therapeutic agents can influence the risk of cancer. We studied the antiproliferative effect of these therapeutic agents (and substances structurally correlated) on Chinese hamster ovary (CHO)-K1 cell growth. Among the compounds tested, apomorphine proved to be the most potent inhibitor of CHO-K1 cell growth, with an EC50 of 3.35 ± 0.12 μM. The apomorphine analogues, apocodeine and hydroxyethylnorapomorphine, were less active as inhibitors of CHO-K1 cell growth. The activity of DA, 6-hydroxydopamine (6-OHDA), phe-nylethylamine (PEA), L-DOPA and bromocriptine as antiproliferative was one order of magnitude lower than that of apomorphine while pergolide was ineffective. To test whether or not the oxidative potential of these compounds was important for their antiproliferative effect, several antioxidants were assayed. Among them, glutathione (GSH) and dithio-threitol (DTT) were effective in reversing the antiproliferative effect of apomorphine, DA, 6-OHDA and PEA, conversely they did not work with bromocriptine. GSH and DTT are sulphydryl-reducing agents; while their effect could explain the efficacy against apomorphine, DA and 6-OHDA, it is difficult to understand why they should have any effect on PEA as this substance does not react with sulphydryl groups. The oxidative potential as a mechanism of action was also questioned by the results obtained with dihydrorhodamine 123, a probe that changes its fluorescent emission wave when oxidized. None of the compounds, with the exception of 6-OHDA, had any effect on the fluorescent emission wave of the probe at the maximal concentrations used to inhibit CHO-K1 cell growth. At concentrations five times higher, apomorphine and DA generated reactive oxygen species but PEA and bromocriptine did not. These data demonstrate that the antiproliferative effect of these compounds is not due to their oxidative potential, but another mechanism must be postulated.

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Abbreviations

L-DOPA:

L-β-3,4-dihydroxyphenylalanine

DA:

dopamine

CHO:

Chinese hamster ovary

6-OHDA:

6-hydroxydopamine

PEA:

phenylethylamine

GSH:

glutathione

DTT:

dithiothreitol

MAO:

monoamine oxidase

DOPAC:

3,4-dihydroxyphenylacetic acid

BHA:

butylated hydroxyanisole

DMEM:

Dulbecco’s modified Eagle’s medium

EGF:

epidermal growth factor

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Authors and Affiliations

  1. Department of Neuroscience, University of Pisa, Via Roma, 55-56126, Pisa, Italy

    Roberto Maggio, Marianna Armogida, Marco Scarselli, Federica Salvadori, Carla Pardini, Serena Chiacchio, Francesca Vaglini & Giovanni U. Corsini

  2. Department of Physiology and Biochemistry, University of Pisa, Via Roma, 55-56126, Pisa, Italy

    Biancamaria Longoni

  3. Ely Lilly Italia & Co, Sesto Florentino, Italy

    Anna Colzi

  4. Institute of Pharmacology, Faculty of Medicine, University of Catania, Italy

    Andrea Chiarenza & Renato Bernardini

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  1. Roberto Maggio
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  2. Marianna Armogida
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Correspondence to Roberto Maggio.

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Maggio, R., Armogida, M., Scarselli, M. et al. Dopamine agonists and analogues have an antiproliferative effect on CHO-K1 cells. neurotox res 1, 285–297 (1999). https://doi.org/10.1007/BF03033258

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