Novel sugar-cholestanols as anticancer agents against peritoneal dissemination of tumor cells |
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Authors: | Shinji Hahismoto Shin Yazawa Takayuki Asao Ahmad Faried Toyo Nishimura Kaori Tsuboi Takashi Nakagawa Takahito Yamauchi Noriyuki Koyama Ken Umehara Abbi R Saniabadi Hiroyuki Kuwano |
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Institution: | Department of General Surgical Science (Surgery I), Graduate School of Medicine, Gunma University, Maebashi, Japan. |
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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. |
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Keywords: | Sugar-cholestanols Apoptosis Peritoneal dissemination Anticancer agent Colorectal cancer |
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