RESUMO
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.
Assuntos
Antineoplásicos/farmacologia , Colestanóis/farmacologia , Neoplasias Experimentais/tratamento farmacológico , Oligossacarídeos/farmacologia , Animais , Antineoplásicos/síntese química , Western Blotting , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Colestanóis/síntese química , Cromatografia Líquida , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/metabolismo , Neoplasias Colorretais/patologia , Citocromos c/metabolismo , Fragmentação do DNA/efeitos dos fármacos , Feminino , Células HT29 , Humanos , Injeções Intraperitoneais , Camundongos , Camundongos Endogâmicos BALB C , Transplante de Neoplasias/métodos , Neoplasias Experimentais/metabolismo , Neoplasias Experimentais/patologia , Oligossacarídeos/síntese química , Neoplasias Gástricas/tratamento farmacológico , Neoplasias Gástricas/metabolismo , Neoplasias Gástricas/patologia , Espectrometria de Massas em TandemRESUMO
The understanding of the cell signaling pathways and the molecular events leading to cell death of cancer cells will provide in-depth perspective into the identification and development of potent anticancer agents. A balance between cell proliferation and cell death has been raised as a rational target for the management of malignant tumors. In the present study, the authors demonstrated that chemically synthesized sugar-cholestanols consisting of GlcNAcbeta-, Galbeta- and GlcNAcbeta1,3Galbeta-cholestanols exerted a strong inhibiting activity against cell proliferation of esophageal cancer cells, but cholestanol itself did not show such an activity against the same cancer cells at all. In addition to their predominant role as an antiproliferation agent, evidence based on the molecular analyses suggested that sugar-cholestanols played a regulatory role in multiple signal transduction pathways inducing apoptosis through both the death signal-extrinsic and the mitochondria-intrinsic pathways. Sugar-cholestanols seemed to be more susceptible to esophageal cancer cells than to non-cancerous esophageal cells at the very early event of their exposure and, further, to suppress specifically the expression of vascular endothelial growth factor. Taken together, these novel functions of sugar-cholestanols indicate that they could have promising therapeutic potential against human esophageal cancer.
