In vitro and in silico studies on anticancer activities of alginate oligosaccharide in Epstein-Barr virus-positive nasopharyngeal carcinoma.

Alginate oligosaccharides (AOS) have recently shown promising activities in inhibiting tumour growth in osteosarcomas. It is, however, unknown if AOS is also effective against nasopharyngeal carcinoma (NPC). To this end, the antiproliferation activities of enzymatically derived AOS were investigated against the EBV-positive NPC cell line, C666-1. MTT cytotoxicity assays revealed an antiproliferation effect against the C666-1 cell line, albeit at concentrations above 10 mg/mL, but promoting growth at lower concentrations. As a potential heparin sulfate analog, which also demonstrates a similar biphasic effect on cell proliferation, it was hypothesized that AOS may act on fibroblast growth factors (FGFs) and their receptors (FGFR) like heparin. This hypothesis was supported by in silico molecular docking, which discovered a similar binding pattern between AOS pentasaccharide and heparin pentasaccharide on FGF2, FGFR1 and FGF2-FGFR1 complex. Furthermore, all-atomic molecular dynamics simulations revealed that only the AOS pentasaccharide can pre-form the FGFR1 dimer for binding by FGF2 when one AOS molecule per FGFR1 dimer was simulated, while other AOS models (DP2-DP4) deformed the FGFR1 dimer to disfavour FGF2 binding during the simulations. In contrast, all AOS models (DP2-DP5) deformed the FGFR1 dimer when two AOS molecules per FGFR1 dimer were simulated without FGF2. These results suggest that the observed biphasic effects on cell proliferation by the AOS mixture may be attributed to the binding of the AOS pentasaccharide to the FGFR1/FGF2 proteins, although further experiments to validate this in silico observation are warranted.