Clinical potential of chemically synthesized sugar-cholestanol compounds targeting multiple signaling pathways to induce apoptotic cell death in esophageal cancer
Authors: Ahmad Faried, Leri Faried, Hiroyuki Kuwano, Shin Yazawa
Journal: Clinical Cancer Research (2007)

B27    Introduction : The major challenge in the war against cancer is the specific targeting of the cancer cells. Our previous observation showed that sugar-compounds had anticancer effect for a series of mouse and human cancer cells. 1,2  In this study, we evaluated sugar-cholestanols as an anticancer agent and elucidated the molecular basis of these compounds to induce apoptosis and affecting multiple signaling pathways in cancer and non-cancer esophageal cells.   M  aterials and m  ethods : Sugar-cholestanols consisting of mono- and di-saccharides such as GlcNAc, Gal, Fuc and GlcNAcGal were chemically synthesized through attaching to β-cholestanol as an aglycon at the reducing-end. Cyclodextrin clathrated compounds were then prepared from each sugar-cholestanol and cholestanol only as a control using hydroxypropyl-β- cyclodextrin. Anticancer potential against mouse and human cancer cells was evaluated by the proliferation inhibition assay under the presence of various amounts of these compounds. Further, molecular based changes to induce apoptosis and other pathways were examined by Western blotting of cell lysate from cancer and non-cancerous cells treated with the compounds.   Results : All the cyclodextrin-clathrated sugar-cholestanols showed inhibiting activities of cell proliferation of mouse and human cancer. 1,2  In particular, GlcNAc and GlcNAcGal derivates possessed strong activities when compared with Fuc and Gal derivates. By increasing the concentration of the sugar-cholestanol, the viability of cancer cells was found to decrease significantly, together with the occurrence of apoptotic changes in the cells. Surprisingly, such changes were hardly induced by cholestanol itself even at the highest concentration given (1mM). When cancer cells were treated with GlcNAcGalChol and GlcNAcChol at 20μM, these sugar-cholestanols were found to be taken into a cell and was associated with the following molecular-based changes: Activation of p53 pathways (at Serine 46), along with activation both intrinsic and extrinsic-pathways of caspases cascade and PARP as a hall mark of apoptosis. The DNA ladders of the nucleic fragmentation were observed at the same time in these cells except in non-cancerous cells. Further, our compounds specifically suppress the expression of VEGF-A, and disturb the capillary-like formation on HUVECs, as a model of angiogenesis  in vitro , in dose and time-dependent manner. 3   Conclusion:  Newly synthesized sugar-cholestanols have been demonstrated to induce apoptosis in mouse and human cancer cells. Although the mechanism of such an induction with GlcNAcGal and GlcNAcβRChol is not fully elucidated, it must be involved in the multiple signaling pathways to induced apoptosis. This novel feature of glycoconjugates with cholestanol should have clinical application as a promising anticancer agent for prevention and treatment of malignant diseases, especially esophageal cancer, in the near future.   R  eferences:  1. Hashimoto S.,  et al. Glycoconjugate Journal , 22: 311, 2005.  2. Faried A.,  et al .  Angiogenesis in Cancer and Vascular Disease , 17: 103, 2006.  3. Faried A.,  et al .  Cancer Science , 98: 1358-1367, 2007.