Interference with the CXCL12/CXCR4 axis as potential antitumor strategy: superiority of a sulfated galactofucan from the brown algaSaccharina latissimaand Fucoidan over heparins

Abstract

The present study demonstrates that fucose-containing sulfated polysaccharides (FCSP) from brown algae interfere with the CXCL12/CXCR4 axis in human Burkitt's lymphoma cells by binding CXCL12 and thereby blocking both CXCL12-induced CXCR4 receptor activation and downstream effects like migration and secretion of matrix metalloproteinase-9. This mode of action is currently considered as promising strategy for tumor therapy and may contribute to the known in vivo antitumor, antimetastatic and antiangiogenic activity of FCSP. In terms of the inhibition of the CXCR4 activation, FCSP from Saccharina latissima (S.l.-FCSP) proved to be more active than a commercial "Fucoidan" from Fucus vesiculosus, and both FCSP were superior to heparins by more than one order of magnitude. Fractionation of S.l.-FCSP revealed that its main fraction is composed of a homogeneous, higher sulfated galactofucan (S.l.-SGF) which consistently exhibited stronger activities and can therefore be considered as the active ingredient of S.l.-FCSP. By subjecting Fucoidan to the same fractionation procedure, the inhibitory activity of the obtained purified Fucoidan on the CXCL12/CXCR4 axis tended to be weaker and its antioxidant and antiproliferative effects were lost. This was probably due to the separation of contaminants including phenolic compounds, whose content additionally showed marked batch-to-batch variability. Regarding the need of standardized, well-characterized FCSP preparations for any potential medical application, our results indicate that S.l.-SGF is a promising candidate for further investigations and that S. latissima may be a more appropriate source of FCSP than F. vesiculosus or other algae species with high contents of co-extractable compounds.

The Antioxidant Activity of Polysaccharides Derived from Marine Organisms: An Overview

“…Low-molecular-weight polysaccharide DHmG-3 with its primary structure and sulfate retained could be obtained by degrading Holothuria mexicana glycosaminoglycans (HmG) with H 2 O 2 /ascorbic acid, and it showed moderate scavenging ability to superoxide radicals and hydroxyl radicals, which was lower than DHmG (Table 1) [69]. The weak antioxidant activity of DHmG-3 may be explained by the remove of phenolic substance in HmG with the treatment of H 2 O 2 [135,136]. In addition, the polysaccharides isolated from sea cucumber by the alkali extraction method have moderate antioxidant activity (Table 1) [67].…”

Phycochemical Constituents and Biological Activities of Fucus spp.

“…For example, in vitro antiproliferative effect of F. vesiculosus fucoidan towards melanoma B16 cells or human lymphoma HS-Sultan cells was shown to result from the triggering of caspase 3 [98,99], while on MCF-7 breast cancer cells, HeLa cervical epithelioid cells and HT-29 human colon cancer cells, apoptotic chain reaction was initiated by activation of caspases 8 and/or 9 [100,101,102]. In A549 lung carcinoma cells and Raji cells, F. vesiculosus fucoidan was found to suppress the expression of matrix metalloproteinase 2 and 9, respectively [103,104], while fucoidans from F. serratus , F. distichus , and F. vesiculosus were shown to block the formation of platelet-tumor aggregates, i.e., a mechanism of tumor cells transportation and fixation in the metastatic site, of a highly metastatic MDA-MB-231 breast cancer cells [96], thus preventing the tumor dissemination and metastization. Additionally, as Fucus spp.…”

Therapies from Fucoidan: An Update

“…The binding of these receptors can be critical for the establishment, growth and metastasis of tumors, so prevention of binding may assist in inhibiting cancer. Since Kwak’s review which also discussed this subject, fucoidan from Saccharina latissimi and Fucus vesiculosus and heparin were investigated for their effects on human Burkitt’s lymphoma cells [ 70 ]. The fucoidan fractions bound CXCL12, and thus prevented CXCR4 binding and the downstream effects such as secretion of matrix-degrading enzymes necessary for metastasis.…”