The natural compound fucoidan from New Zealand Undaria pinnatifida synergizes with the ERBB inhibitor lapatinib enhancing melanoma growth inhibition

Abstract

Melanoma remains one of the most aggressive and therapy-resistant cancers. Finding new treatments to improve patient outcomes is an ongoing effort. We previously demonstrated that melanoma relies on the activation of ERBB signaling, specifically of the ERBB3/ERBB2 cascade. Here we show that melanoma tumor growth is inhibited by 60% over controls when treated with lapatinib, a clinically approved inhibitor of ERBB2/EGFR. Importantly, tumor growth is further inhibited to 85% when the natural compound fucoidan from New Zealand U. pinnatifida is integrated into the treatment regimen. Fucoidan not only enhances tumor growth inhibition, it counteracts the morbidity associated with prolonged lapatinib treatment. Fucoidan doubles the cell killing capacity of lapatinib. These effects are associated with a further decrease in AKT and NFκB signaling, two key pathways involved in melanoma cell survival. Importantly, the enhancing cell killing effects of fucoidan can be recapitulated by inhibiting ERBB3 by either a specific shRNA or a novel, selective ERBB3 neutralizing antibody, reiterating the key roles played by this receptor in melanoma. We therefore propose the use of lapatinib or specific ERBB inhibitors, in combination with fucoidan as a new treatment of melanoma that potentiates the effects of the inhibitors while protecting from their potential side effects.

Fucoidan Does Not Exert Anti-Tumorigenic Effects on Uveal Melanoma Cell Lines

“…Fucoidan is also under investigation to be used in combination with other chemotherapeutic drugs in order to enhance their efficacy, as seen in e.g., melanoma [ 44 ] or breast cancer cells [ 43 ], where pro-apoptotic or anti-proliferative effects of the chemotherapeutics are enhanced by fucoidan. The results found in our study cannot be extrapolated towards combination treatments, however, the effect of fucoidan in combination treatments is also cell type dependent and may reduce the efficacy of the chemotherapeutic compound [ 45 ].…”

Fucoidan Extracted from Undaria pinnatifida: Source for Nutraceuticals/Functional Foods

“…Similar observations are reported by Honya et al [ 32 ] and Fletcher et al [ 33 ]. A New Zealand study also found that sulfate content in the extracted fucoidan increased more than twice within a 4-month period, while fucose content remains constant [ 34 ].…”

“…The anticancer activity of fucoidan is influenced by its sulfate content; low molecular weight fucans isolated from Ascophyllum nodosum exhibited increased antiproliferative activity on fibroblast cell line CCL39 with increased sulfate content [ 33 ]. Likewise, oversulfated fucoidan from F. vesiculosus exhibited higher anti-angiogenesis potency on the growth of B16 melanoma cells, Lewis lung carcinoma, and Sarcoma 180 cell lines [ 34 ]. This suggests that the sulfate content of fucoidan may be critical in influencing its anticancer activity.…”

“…This highlighted the potential of fucoidan as a source of antioxidant. Fucoidans extracted from U. pinnatifida from mussel farms in New Zealand, exhibit strong antioxidant activities using the DPPH scavenging and CUPRAC assays [ 34 ]. Another recent study prospects fucoidan from U. pinnatifida as a potential antioxidant that can effectively abrogate oxidative stress, too [ 41 ].…”

Potencjał fukoidyny jako środka wspomagającego w terapii onkologicznej

“…Udowodniono również, że powyższy rezultat wynikał z dezaktywacji ścieżek sygnałowych zależnych od Akt i NF-kB, kluczowych dla wzrostu i proliferacji komórek czerniaka. Ponadto wykazano, że suplementacja fukoidyną myszy leczonych lapanitibem osłabia wywołany terapią spadek masy ciała i obniża częstość występowania poważnych działań niepożądanych, jednocześnie wykazując synergię z lapanitibem [18]. Skuteczność kombinacji lapanitibu i fukoidyny badana była również z wykorzystaniem innych linii komórkowych charakteryzujących się podwyższonym poziomem ekspresji receptora naskórkowego czynnika wzrostu EGFR (ang.…”