INVESTIGADORES
ALONSO Daniel Fernando
artículos
Título:
Enhanced cytostatic activity of statins in mouse mammary carcinoma cells overexpressing β2-chimaerin
Autor/es:
P LORENZANO MENNA; RL PARERA; GA CARDAMA; DF ALONSO; DE GOMEZ; HG FARINA
Revista:
MOLECULAR MEDICINE REPORTS
Editorial:
SPANDIDOS PUBL LTD
Referencias:
Año: 2009 vol. 2 p. 97 - 102
ISSN:
1791-2997
Resumen:
The statins, a family of cholesterol-lowering drugs, are known to block
the formation of isoprenoids. They thus affect the small GTPase Rho,
which requires attachment to cell membranes for proper signaling
activity. Chimaerins are GTPase-activating proteins (GAPs) that
accelerate GTP hydrolysis from Rac, another GTPase of the same family.
We explored the cooperative antitumor effects of the overexpression of
β2-chimaerin in combination with statins. F3II mouse mammary carcinoma
cells transfected with the β2-chimaerin GAP domain exhibiting low
intracellular levels of active Rac-GTP were exposed in vitro to a panel
of statins. Transfectants were significantly more sensitive to the
cytostatic effects of lovastatin, simvastatin, atorvastatin and
rosuvastatin than untransfected F3II cells with high Rac-GTP levels.
Transfected tumor cells also showed a higher sensitivity for detachment
from the substrate and for apoptosis after statin exposure. We further
checked the cytostatic effect of statins in combination with
azathioprine, a compound that specifically blocks Rac1 activation.
Combined treatment with simvastatin and azathioprine demonstrated an
enhanced growth-inhibitory effect on control F3II cells. Our data
suggest that the combination of statins with a reduction in active Rac
levels can produce a cooperative antitumor effect on breast cancer
cells.