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Carcinogenesis Advance Access published online on February 10, 2005
Carcinogenesis, doi:10.1093/carcin/bgi036
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© The Author 2005. Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oupjournals.org
Received July 21, 2004
Revised January 25, 2005
Accepted January 26, 2005

CANCER BIOLOGY

Statins activate the mitochondrial pathway of apoptosis in human lymphoblasts and myeloma cells

Paola Cafforio 1, Franco Dammacco 1, Angela Gernone 1, and Franco Silvestris 1*

1 Department of Internal Medicine and Oncology (DIMO), University of Bari, P.za Giulio Cesare, 11 - 70124 Bari, Italy

* To whom correspondence should be addressed.
Franco Silvestris, E-mail: f.silvestris{at}dimo.uniba.it


  Abstract

Although statins are lipid-lowering drugs that block cholesterol biosynthesis, they exert immunomodulatory, anti-inflammatory, anti-angiogenic and anti-proliferative functions by reducing the isoprenylation of proteins involved in cell signal transduction such as Ras and RhoA. In this study, we provide evidence that several natural (lovastatin, simvastatin, pravastatin) and synthetic (cerivastatin and atorvastatin) statins exert a cytotoxic effect on human T, B and myeloma tumor cells by promoting their apoptosis. Dissimilar susceptibility to apoptosis has been detected in these lines, presumably in relation to the altered expression of proteins involved in the regulation of cellular signals. Cerivastatin promptly activated the cell death even in doxorubicin resistant cell lines such as MCC-2, whereas pravastatin, a hydrophilic compound, failed to induce any effect on either proliferation or apoptosis. The statin-induced apoptotic pathway in these cell lines was presumably regulated by altered prenylation of either Ras or RhoA, as measured by the defective membrane localization of these small GTPases. In addition the cell proliferation was rescued by both farnesylpyrophosphate (FPP) and geranyl-geranylpyrophosphate (GGPP), whereas no effect was obtained with the squalene, a direct precursor of cholesterol. Statins primed apoptosis through its intrinsic pathway by mitochondria involvement. In fact, we observed the reduction of mitochondrial membrane potential and the cytosolic release of the second mitochondria-derived activator of caspases (Smac/DIABLO). The apoptotic pathway was caspase-dependent since caspases 9, 3 and 8 were efficiently activated. These results support the potential use of statins in association to conventional treatment as apoptosis-triggering agents in those tumors.

Keywords: caspases; cytotoxicity; HMG-CoA reductase inhibitors; isoprenylation; signal transduction.
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