Estrogenic effect of procymidone through activation of MAPK in MCF-7 breast carcinoma cell line.
Procymidone modifies sexual differentiation in vitro and induces estrogenic activity in primary cultured rainbow trout hepatocytes, as shown by an increase in the contents of vitellogenin and heat shock proteins. Since this dicarboximide fungicide is found in human tissues, it was considered of interest to investigate its ability to induce endocrine damage in the MCF-7 human cell line. The mechanism of this estrogenic action was also evaluated. Procymidone 100 microM stimulated cell growth from day 3 up to day 12 and raised the level of pS2 on day 3. Although procymidone does not bind the estrogen receptor (ER), the antiestrogen ICI 182780 inhibited its effect on cell growth and pS2 content, suggesting that the ER is involved indirectly in these effects. In exploring the mechanism of ER indirect activation we found that the antibody against c-Neu receptor (9G6) did not modify procymidone's effects on cell growth and pS2 expression. Thus, procymidone does not bind the c-Neu membrane receptor, excluding this indirect ER activation pathway. We also found that procymidone induced mitogen-activated protein kinase (MAPK) at 15 and 30 min, and that PD 98059, a MAPK (Erk1/2) inhibitor, prevented procymidone's effects on cell growth and pS2, indicating that MAPK activation is responsible for procymidone ER activation. The production of reactive oxygen species (ROS) with these times and elimination of the phenomenon by alpha-tocopherol (alpha-T), a ROS scavenger, is proof that oxygen free-radical production is at the basis of the MAPK activation by procymidone.
Radice
Sonia
S
Department of Pharmacology, Chemotherapy and Medical Toxicology E. Trabucchi, University of Milan, Via Vanvitelli 32, 20129 Milan, Italy. sonia.radice@unimi.it
Chiesara
Enzo
E
Frigerio
Silvia
S
Fumagalli
Roberta
R
Parolaro
Daniela
D
Rubino
Tiziana
T
Marabini
Laura
L
D001943:Breast Neoplasms / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D001643:Bridged Bicyclo Compounds / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004338:Drug Combinations; D004790:Enzyme Induction / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004968:Estrogens, Non-Steroidal / Q000494:pharmacology*; D005260:Female; D005419:Flavonoids / Q000494:pharmacology; D005659:Fungicides, Industrial / Q000494:pharmacology*; D006133:Growth Substances / Q000378:metabolism; D006801:Humans; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000096:biosynthesis*; D017382:Reactive Oxygen Species / Q000378:metabolism; D000071163:Trefoil Factor-1; D025521:Tumor Suppressor Proteins / Q000378:metabolism; D024502:alpha-Tocopherol / Q000494:pharmacology
D001643:Bridged Bicyclo Compounds; D004338:Drug Combinations; D004791:Enzyme Inhibitors; D004968:Estrogens, Non-Steroidal; D005419:Flavonoids; D005659:Fungicides, Industrial; D006133:Growth Substances; D017382:Reactive Oxygen Species; C051838:TFF1 protein, human; D000071163:Trefoil Factor-1; D025521:Tumor Suppressor Proteins; D020928:Mitogen-Activated Protein Kinases; C035988:procymidone; D024502:alpha-Tocopherol; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one