Novel sugar-cholestanols as anticancer agents against peritoneal dissemination of tumor cells.
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.
Hahismoto
Shinji
S
Department of General Surgical Science (Surgery I), Graduate School of Medicine, Gunma University, Maebashi, Japan.
Yazawa
Shin
S
Asao
Takayuki
T
Faried
Ahmad
A
Nishimura
Toyo
T
Tsuboi
Kaori
K
Nakagawa
Takashi
T
Yamauchi
Takahito
T
Koyama
Noriyuki
N
Umehara
Ken
K
Saniabadi
Abbi R
AR
Kuwano
Hiroyuki
H
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
D000970:Antineoplastic Agents; D002777:Cholestanols; D009844:Oligosaccharides; D045304:Cytochromes c