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Originally published online as doi:10.2353/ajpath.2009.080551 on January 29, 2009

Published online before print January 29, 2009
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(American Journal of Pathology. 2009;174:1017-1026.)
© 2009 American Society for Investigative Pathology
DOI: 10.2353/ajpath.2009.080551

Ezetimibe Is an Inhibitor of Tumor Angiogenesis

Keith R. Solomon*{dagger}{ddagger}, Kristine Pelton{dagger}, Kelly Boucher{dagger}, Jinsoo Joo{dagger}, Christopher Tully{dagger}, David Zurakowski{dagger}, Carl P. Schaffner§, Jayoung Kim{ddagger} and Michael R. Freeman{ddagger}¶||

From the Departments of Orthopaedic Surgery,* Surgery, and Biological Chemistry and Molecular Pharmacology,|| Harvard Medical School, Boston, Massachusetts; the Departments of Orthopaedic Surgery,{dagger} and Urology,{ddagger} Children’s Hospital Boston, Boston, Massachusetts; and the Department of Microbiology and Biochemistry,§ Waksman Institute, Rutgers, the State University of New Jersey, New Brunswick, New Jersey

Epidemiological and preclinical observations have suggested a role for one or more products of the mevalonate/cholesterol biosynthesis pathway in the progression of prostate cancer. In this study, we used ezetimibe (Zetia), a specific, FDA-approved, cholesterol uptake-blocking drug, in combination with either a hyper- or hypocholesterolemic diet, to show that elevated circulating cholesterol levels promote, whereas a reduction in circulating cholesterol levels retard, the growth of human prostate cancer xenograft tumors in mice. Circulating cholesterol levels also modified tumor angiogenesis; higher cholesterol levels increased microvessel density and other indicators of vascularity. Consistent with these data, the reduction of cholesterol levels also increased the levels of the angiogenesis inhibitor thrombospondin-1 in the xenografts. Our results thus suggest that hypercholesterolemia directly accelerates the growth of prostate carcinomas, and that the pharmacological reduction of serum cholesterol levels may retard prostate cancer growth by inhibiting tumor angiogenesis.


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