Cilostazol reduces proliferation through c-Myc down-regulation in MDCK cells.
Cilostazol, a drug commonly used in the treatment of intermittent claudication is a selective phosphodiesterase III inhibitor. It affects cell proliferation, increases cAMP levels, activates the cyclic AMP-dependent protein kinase and inhibits E2F in vascular cells. Polycystic kidney disease, a common genetic disorder, is characterized by increased cell proliferation, basement membrane abnormalities and fluid secretion. An established in vitro model of this disease is the canine Madin-Darby cell line (MDCK). In this communication, we investigated the effects of cilostazol exposure in MDCK cells. A reduced cell proliferation rate with an arrest in the G1 phase of the cell cycle was detected. Accordingly, several transcription factors associated with cell cycle control were affected by cilostazol, particularly c-myc. c-Myc DNA binding as well as its transcriptional activity was severely impaired in cilostazol-treated cells. Pharmacological tools demonstrated that besides the involvement of the cyclic AMP-dependent protein kinase, the extracellular signal-regulated kinases I/II participate in the response. These results suggest that cilostazol inhibits cell proliferation through c-myc transcriptional control, also pave the way to our better understanding of molecular transactions triggered by this drug and strengthen its potential use in other malignancies.
Muñoz
Balam
B
Departamento de Genética y Biología Molecular, Centro de Investigación y de Estudios Avanzados del Instituto Politécnico Nacional, México, DF 07000, México.
Huerta
Miriam
M
López-Bayghen
Esther
E
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001483:Base Sequence; D002453:Cell Cycle / Q000187:drug effects; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects; D000077407:Cilostazol; D000242:Cyclic AMP / Q000378:metabolism; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D004247:DNA / Q000378:metabolism; D018450:Disease Progression; D004285:Dogs; D015536:Down-Regulation / Q000187:drug effects*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D006801:Humans; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D007690:Polycystic Kidney Diseases / Q000188:drug therapy / Q000378:metabolism; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics* / Q000378:metabolism; D013777:Tetrazoles / Q000494:pharmacology* / Q000627:therapeutic use; D014157:Transcription Factors / Q000378:metabolism
D010726:Phosphodiesterase Inhibitors; D016271:Proto-Oncogene Proteins c-myc; D013777:Tetrazoles; D014157:Transcription Factors; D004247:DNA; D000242:Cyclic AMP; D017868:Cyclic AMP-Dependent Protein Kinases; D048049:Extracellular Signal-Regulated MAP Kinases; D000077407:Cilostazol