title: Avasimibe encapsulated in human serum albumin blocks cholesterol esterification for selective cancer treatment.
abstract: 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 nanoformulation 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.
authors: †Weldon School of Biomedical Engineering, ‡Department of Biological Sciences, §Department of Chemistry, ⊥Center for Cancer Research, ∥Department of Comparative Pathobiology, #Department of Industrial and Physical Pharmacy, Purdue University, West Lafayette, Indiana 47907, United States.
authors: Steve Seung-Young
authors: SS
authors: Lee
authors: †Weldon School of Biomedical Engineering, ‡Department of Biological Sciences, §Department of Chemistry, ⊥Center for Cancer Research, ∥Department of Comparative Pathobiology, #Department of Industrial and Physical Pharmacy, Purdue University, West Lafayette, Indiana 47907, United States.
authors: Junjie
authors: J
authors: Li
authors: †Weldon School of Biomedical Engineering, ‡Department of Biological Sciences, §Department of Chemistry, ⊥Center for Cancer Research, ∥Department of Comparative Pathobiology, #Department of Industrial and Physical Pharmacy, Purdue University, West Lafayette, Indiana 47907, United States.
authors: Jien Nee
authors: JN
authors: Tai
authors: †Weldon School of Biomedical Engineering, ‡Department of Biological Sciences, §Department of Chemistry, ⊥Center for Cancer Research, ∥Department of Comparative Pathobiology, #Department of Industrial and Physical Pharmacy, Purdue University, West Lafayette, Indiana 47907, United States.
authors: Timothy L
authors: TL
authors: Ratliff
authors: †Weldon School of Biomedical Engineering, ‡Department of Biological Sciences, §Department of Chemistry, ⊥Center for Cancer Research, ∥Department of Comparative Pathobiology, #Department of Industrial and Physical Pharmacy, Purdue University, West Lafayette, Indiana 47907, United States.
authors: Kinam
authors: K
authors: Park
authors: †Weldon School of Biomedical Engineering, ‡Department of Biological Sciences, §Department of Chemistry, ⊥Center for Cancer Research, ∥Department of Comparative Pathobiology, #Department of Industrial and Physical Pharmacy, Purdue University, West Lafayette, Indiana 47907, United States.
authors: Ji-Xin
authors: JX
authors: Cheng
mesh_terms: D000081:Acetamides; D000085:Acetates / Q000097:blood / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology*; D000818:Animals; D000970:Antineoplastic Agents / Q000097:blood / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D001682:Biological Availability; D002214:Capsules; D002470:Cell Survival / Q000187:drug effects; D002626:Chemistry, Pharmaceutical; D002784:Cholesterol / Q000378:metabolism*; D004951:Esterification / Q000187:drug effects; D006801:Humans; D008297:Male; D051379:Mice; D012449:Safety; D012709:Serum Albumin / Q000737:chemistry*; D002785:Sterol O-Acyltransferase / Q000037:antagonists & inhibitors / Q000378:metabolism; D013449:Sulfonamides; D013451:Sulfonic Acids / Q000097:blood / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology*; D014867:Water / Q000737:chemistry
chemical_list: D000081:Acetamides; D000085:Acetates; D000970:Antineoplastic Agents; D002214:Capsules; D012709:Serum Albumin; D013449:Sulfonamides; D013451:Sulfonic Acids; D014867:Water; C423185:avasimibe; D002784:Cholesterol; D002785:Sterol O-Acyltransferase; C493492:sterol O-acyltransferase 1
keywords: ACAT-1 inhibitor; avasimibe; cancer; cholesterol; cholesteryl ester; human serum albumin