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Reduction of mouse mammary tumor formation and metastasis by lovastatin, an inhibitor of the mevalonate pathway of cholesterol synthesis

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Abstract

Lovastatin, a fungal antibiotic used in the treatment of hypercholesterolemia, is an inhibitor of 3-hydroxy-3-methylglutaryl coenzyme A reductase, the key regulatory enzyme in the mevalonate pathway of cholesterol synthesis. We examined the antitumor properties of lovastatin on the F3II sarcomatoid mammary carcinoma, a highly invasive and metastatic murine tumor model. Female BALB/c inbred mice were inoculated subcutaneously with F3II tumor cells and injected i.p. daily with 10 mg/kg body weight of lovastatin or administered p.o. at a level corresponding to the human dosage of 1–2 mg/kg/day. Treatment significantly prolonged tumor latency and reduced tumor formation and metastatic dissemination to the lungs from established mammary tumors. In vitro, antitumor properties of lovastatin were strongly associated with inhibition of tumor cell attachment and migration. These actions were prevented by addition of mevalonate but not by equivalent concentrations of farnesyl pyrophosphate. In accordance, Western blot assays showed that lovastatin effects did not appear to be related to modifications in Ras oncoproteins in our model. The present data indicate that lovastatin could be an antitumor agent with potentially useful clinical applications in breast cancer.

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Authors and Affiliations

  1. Laboratory of Molecular Oncology, Department of Science and Technology, Quilmes National University, Buenos Aires, Argentina

    Daniel F. Alonso, Hernán G. Farina, Guillermo Skilton, Mariano R. Gabri, Mariana S. De Lorenzo & Daniel E. Gomez

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  1. Daniel F. Alonso
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  2. Hernán G. Farina
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  3. Guillermo Skilton
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  4. Mariano R. Gabri
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  5. Mariana S. De Lorenzo
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  6. Daniel E. Gomez
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Alonso, D.F., Farina, H.G., Skilton, G. et al. Reduction of mouse mammary tumor formation and metastasis by lovastatin, an inhibitor of the mevalonate pathway of cholesterol synthesis. Breast Cancer Res Treat 50, 83–93 (1998). https://doi.org/10.1023/A:1006058409974

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