title: Novel sugar-cholestanols as anticancer agents against peritoneal dissemination of tumor cells.
abstract: Chemically synthesized sugar-cholestanols with mono-, di-, and tri-saccharides attached to cholestanol showed strong inhibiting activity against the proliferation of colorectal and gastric cancer cells. In contrast, cholestanol without sugar moieties was totally ineffective. Furthermore, when cancer cells were exposed to GlcNAcRbetacholestanol (R=(-) or beta1-3Gal), the compound was rapidly taken up via the lipid rafts/microdomains on the cell surface. The uptake of sugar-cholestanol in mitochondria increased gradually and was followed by the release of cytochrome c from mitochondria and the activation of apoptotic signals through the mitochondrial pathway and the caspase cascade, leading to apoptotic cell death, characterized by DNA ladder formation and nuclear fragmentation. Additionally, the examination of GlcNAcRbetacholestanol in a mouse model of peritoneal dissemination showed a dramatic reduction of tumor growth (P < 0.003) and prolonged mouse survival time (P<0.0001). Based on these observations, we believe that the sugar-cholestanols described here have clinical potential as novel anticancer agents.
authors.affiliation: Department of General Surgical Science (Surgery I), Graduate School of Medicine, Gunma University, Maebashi, Japan.
authors.forename: Shinji
authors.initials: S
authors.lastname: Hahismoto
authors.forename: Shin
authors.initials: S
authors.lastname: Yazawa
authors.forename: Takayuki
authors.initials: T
authors.lastname: Asao
authors.forename: Ahmad
authors.initials: A
authors.lastname: Faried
authors.forename: Toyo
authors.initials: T
authors.lastname: Nishimura
authors.forename: Kaori
authors.initials: K
authors.lastname: Tsuboi
authors.forename: Takashi
authors.initials: T
authors.lastname: Nakagawa
authors.forename: Takahito
authors.initials: T
authors.lastname: Yamauchi
authors.forename: Noriyuki
authors.initials: N
authors.lastname: Koyama
authors.forename: Ken
authors.initials: K
authors.lastname: Umehara
authors.forename: Abbi R
authors.initials: AR
authors.lastname: Saniabadi
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Kuwano
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000494:pharmacology*; D015153:Blotting, Western; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002777:Cholestanols / Q000138:chemical synthesis / Q000494:pharmacology*; D002853:Chromatography, Liquid; D015179:Colorectal Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D045304:Cytochromes c / Q000378:metabolism; D053938:DNA Fragmentation / Q000187:drug effects; D005260:Female; D019073:HT29 Cells; D006801:Humans; D007274:Injections, Intraperitoneal; D051379:Mice; D008807:Mice, Inbred BALB C; D009368:Neoplasm Transplantation / Q000379:methods; D009374:Neoplasms, Experimental / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D009844:Oligosaccharides / Q000138:chemical synthesis / Q000494:pharmacology*; D013274:Stomach Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D053719:Tandem Mass Spectrometry
chemical_list: D000970:Antineoplastic Agents; D002777:Cholestanols; D009844:Oligosaccharides; D045304:Cytochromes c