Apomorphine, dopamine and phenylethylamine reduce the proportion of phosphorylated insulin receptor substrate 1.
We tested the ability of dopamine, apomorphine, phenylethylamine and pergolide to inhibit the proliferation of fetal calf serum-stimulated human breast cancer (MCF)-7 cells. While the first three compounds were able to block the proliferation of MCF-7 cells, pergolide failed to do so (up to 100 microM). The inhibitory effect of dopamine, apomorphine and phenylethylamine was also evident in serum-starved insulin-stimulated MCF-7 cells. Apomorphine also inhibited the proliferation of the human oestrogen receptor-negative breast cancer (MDA-MB231) and prostate carcinoma (LNCaP) cell lines. In a second set of experiments, we measured the ability of dopamine, apomorphine, phenylethylamine and pergolide to inhibit the phosphorylation (or increase the dephosphorylation) of the insulin receptor substrate (IRS)-1, a major intracellular substrate of the insulin-like growth factor (IGF)-1 receptor. Dopamine, apomorphine and phenylethylamine all reduced to zero the level of phosphorylated IRS-1 with potencies ranging between 0.01 and 1 microM. Finally, we found that fibroblasts from IRS-1 null (-/-) mice were less sensitive to the anti-proliferative effect of apomorphine compared to fibroblasts from wild type-mice, suggesting that the inhibition of IRS-1 phosphorylation by apomorphine is an important aspect of the activity of this compound.
Chiarenza
A
A
Department of Clinical and Experimental Pharmacology, University of Catania, Catania, Italy.
Scarselli
M
M
Novi
F
F
Lempereur
L
L
Bernardini
R
R
Corsini
G U
GU
Maggio
R
R
D001058:Apomorphine / Q000494:pharmacology*; D002455:Cell Division / Q000187:drug effects; D004298:Dopamine / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D006801:Humans; D055504:Insulin Receptor Substrate Proteins; D010479:Pergolide / Q000494:pharmacology; D010627:Phenethylamines / Q000494:pharmacology*; D010750:Phosphoproteins / Q000378:metabolism*; D010766:Phosphorylation; D014407:Tumor Cells, Cultured
C526292:IRS1 protein, human; D055504:Insulin Receptor Substrate Proteins; C526295:Irs1 protein, mouse; D010627:Phenethylamines; D010750:Phosphoproteins; D010479:Pergolide; D001058:Apomorphine; D004298:Dopamine