Journal
ACS NANO
Volume 9, Issue 3, Pages 2420-2432Publisher
AMER CHEMICAL SOC
DOI: 10.1021/nn504025a
Keywords
ACAT-1 inhibitor; avasimibe; human serum albumin; cholesteryl ester; cholesterol; cancer
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Funding
- DoD Prostate Cancer Research Program Idea Development Award
- [R01 CA129287]
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Undesirable side effects remain a significant challenge in cancer chemotherapy. Here we report a strategy for cancer-selective chemotherapy by blocking acyl-CoA cholesterol acyltransferase-1 (ACAT-1)-mediated cholesterol esterification: To efficiently block cholesterol esterification in cancer in vivo, we developed a systemically injectable nano-formulation of avasimibe (a potent ACAT-1 inhibitor), called avasimin. In cell lines of human prostate, pancreatic, lung, and colon cancer, avasimin significantly reduced cholesteryl ester storage in lipid droplets and elevated intracellular free cholesterol levels, which led to apoptosis and suppression of proliferation. In xenograft models of prostate cancer and colon cancer, intravenous administration of avasimin caused the concentration of avasimibe in tumors to be 4-fold higher than the IC50 value. Systemic treatment of avasimin notably suppressed tumor growth in mice and extended the length of Survival time. No adverse effects Of avasimin to normal cells and organs were observed. Together, this study provides an effective approach for selective Cancer Chemotherapy by targeting altered cholesterol metabolism of cancer cells.
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