Treatment of Prostate Cancer With Fucoidan of Low Molecular Weights in Combination With Guanine-rich Oligonucleotide Therapy
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Three oncogenes, ErbB receptors, Ras proteins and nucleolin, may contribute to malignant transformation of healthy cells. Previously, mutant Ras was shown to be capable of activating ErbB receptors in a ligand-independent manner. Moreover, nucleolin, a transcriptional regulator and ribosome biogenesis factor, could bind both K-Ras and the cytoplasmic tail of ErbB receptors to enhance ErbB receptor activation. Therefore, focus on ErbB receptors and nucleolin are important in improving cancer patient survival. Fucoidan is one of the Fucose-Containing Sulfated Polysaccharides (FCSPs) isolated from various brown seaweeds which are known to possess essential bioactive properties, notably growth inhibitory effects on tumor cells. FCSPs also possess sulfated galactofucans, with backbones built of (1→6)-β-D-galacto- and/or (1→2)-β-D-mannopyranosyl units. In addition to sulfate groups these backbone residues may be substituted with fucosides, single fucose substitutions, and/or glucuronic acid, xylose or glucose substitutions. Fucoidan has remarkable biological activities, especially in terms of anticancer-promoting applications. Previous studies have shown that fucoidan mainly targets the EGFR (ErbB-1)-signaling pathway, which may contribute to fucoidan’s observed chemo-preventive potential. Nucleolin is a ubiquitously expressed acidic phosphoprotein that is involved in important aspects of cell proliferation and cell growth. It is localized primarily to the nucleoli, but it undergoes nuclear cytoplasmic shuttling and is also found on the cell surface of some types of cells. Cell surface nucleolin is found in a wide range of tumor cells, and it is used as a marker for cancer diagnosis. Ronit Pinkas-Kramarski’s lab in Israel has identified non-nucleolar nucleolin as an ErbB receptor-interacting protein. This interaction leads to receptor dimerization and activation as well as to increased colony growth in soft agar. Recent studies have identified a crosstalk between nucleolin, ErbB1 and Ras proteins. Therefore, it seems that combining two drugs, Fucoidan (which inhibits ErbB1) and GroA/AS1411 (which specifically inhibits cell surface nucleolin) may have a better inhibitory effect on ErbB receptor activation and thereby a stronger inhibitory effect on cancer cell growth and tumorogenicity. This study describes the effect of Low-molecular-weight fucoidan (LMWF) and Sigma Fucoidan (SF) used alone or combined with GroA on the proliferation of human prostate cancer cell lines PC-3 and DU-145. LMWF and FS inhibited the growth of these cancer cells in a time- and dose- dependent manner in the present study, but the effect of SF was unsatisfied. Simultaneous combination of LMWF and GroA made an additive inhibitory effect on prostate cancer cell viability. In treatments using SF combined with GroA, SF was not able to enhance the inhibitory effect of GroA on proliferation of PC-3 and DU-145 cells in a concentration dependent manner. Even at very high concentrations, the results of combination SF and GroA treatments only yielded a GroA effect on cell viability. The results may suggest that LMWF can act as a synergistic anti-cancer agent in the treatment of prostate cancer cell lines DU-145 and PC-3, and has the potential to regulate MAPK activity. Combination of LMWF and GroA could have a better inhibitory effect on ErbB receptor activation, and subsequently, a stronger inhibitory effect on cancer cell growth and tumorogenicity. Cell apoptosis and cell cycle analysis conducted by using flow cytometry was also applied to study the mechanism of action of these two drugs. This study provides further evidence that LMWF can affect the cell cycle in sub-G1 phase and leads to cellular apoptosis in PC-3 and DU-145 prostate cancer cell lines. In conclusion, LMWF is a promising natural substance that may be used in combination therapy against cancer, in particular those with ErbB overexpression, such as prostate cancer.