Ezetimibe is an inhibitor of tumor angiogenesis.
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.
Solomon
Keith R
KR
Dept. of Orthopaedic Surgery, Harvard Medical School, Boston, MA 02115, USA. keith.solomon@childrens.harvard.edu
Pelton
Kristine
K
Boucher
Kelly
K
Joo
Jinsoo
J
Tully
Christopher
C
Zurakowski
David
D
Schaffner
Carl P
CP
Kim
Jayoung
J
Freeman
Michael R
MR
D000818:Animals; D000924:Anticholesteremic Agents / Q000627:therapeutic use; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects; D001384:Azetidines / Q000627:therapeutic use*; D016923:Cell Death / Q000187:drug effects; D002784:Cholesterol / Q000494:pharmacology; D000069438:Ezetimibe; D006454:Hemoglobins / Q000378:metabolism; D006801:Humans; D008297:Male; D051379:Mice; D008833:Microcirculation / Q000187:drug effects; D009368:Neoplasm Transplantation; D009389:Neovascularization, Pathologic / Q000517:prevention & control*; D011471:Prostatic Neoplasms / Q000188:drug therapy / Q000473:pathology*; D014183:Transplantation, Heterologous
D000924:Anticholesteremic Agents; D000970:Antineoplastic Agents; D001384:Azetidines; D006454:Hemoglobins; D002784:Cholesterol; D000069438:Ezetimibe