Chemical inhibition of Wip1 phosphatase contributes to suppression of tumorigenesis.
Wip1 is an amplified oncogene whose deletion causes a tumor resistant phenotype in mice. These observations provide justification for a search for Wip1 chemical inhibitors as potential anticancer drugs. Here we report a group of Wip1 inhibitors with anticancer properties both in vitro and in vivo. In vitro, inactivation of Wip1 reduces the proliferation rate of breast cancer cell lines and enhances growth inhibition caused by doxorubicin. In vivo, administration of Wip1 inhibitors decreases proliferation of xenograph tumors and tumors developed in MMTV-c-Neu transgenic mice. We propose that these agents may serve as lead compounds for the development of anticancer drugs targeting Wip1 phosphatase.
Belova
Galina I
GI
Center for Cancer Research, National Cancer Institute, NIH, Bethesda, Maryland, USA.
Demidov
Oleg N
ON
Fornace
Albert J
AJ
Bulavin
Dmitry V
DV
D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000201:enzymology* / Q000517:prevention & control; D002461:Cell Line, Transformed; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002472:Cell Transformation, Viral; D004622:Embryo, Mammalian / Q000166:cytology; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use*; D005260:Female; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism; D011905:Genes, ras; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D020929:Mitogen-Activated Protein Kinase Kinases / Q000378:metabolism; D008968:Molecular Conformation; D009368:Neoplasm Transplantation; D010749:Phosphoprotein Phosphatases / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000302:isolation & purification; D010766:Phosphorylation / Q000187:drug effects; D000071636:Protein Phosphatase 2C; D014183:Transplantation, Heterologous; D023041:Xenograft Model Antitumor Assays
D004791:Enzyme Inhibitors; D020929:Mitogen-Activated Protein Kinase Kinases; C000607458:PPM1D protein, human; D010749:Phosphoprotein Phosphatases; C000607468:Ppm1d protein, mouse; D000071636:Protein Phosphatase 2C