title: 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.
authors.affiliation: Department of Biochemistry, Case Western Reserve University School of Medicine, Cleveland, OH, USA.
authors.forename: Varsha
authors.initials: V
authors.lastname: Thakur
authors.affiliation: School of Science, Auckland University of Technology, New Zealand.
authors.forename: Jun
authors.initials: J
authors.lastname: Lu
authors.affiliation: Takis s.r.l., Rome, Italy.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Roscilli
authors.affiliation: Takis s.r.l., Rome, Italy.
authors.forename: Luigi
authors.initials: L
authors.lastname: Aurisicchio
authors.affiliation: Takis s.r.l., Rome, Italy.
authors.forename: Manuela
authors.initials: M
authors.lastname: Cappelletti
authors.affiliation: Takis s.r.l., Rome, Italy.
authors.forename: Emiliano
authors.initials: E
authors.lastname: Pavoni
authors.affiliation: School of Science, Auckland University of Technology, New Zealand.
authors.forename: William Lindsey
authors.initials: WL
authors.lastname: White
authors.affiliation: Department of Biochemistry, Case Western Reserve University School of Medicine, Cleveland, OH, USA.
authors.forename: Barbara
authors.initials: B
authors.lastname: Bedogni
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D002470:Cell Survival / Q000187:drug effects; D004357:Drug Synergism; D066246:ErbB Receptors / Q000037:antagonists & inhibitors; D006801:Humans; D000077341:Lapatinib; D008297:Male; D008545:Melanoma / Q000188:drug therapy / Q000378:metabolism*; D051379:Mice; D016513:Mice, SCID; D009520:New Zealand; D011134:Polysaccharides / Q000494:pharmacology*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D011799:Quinazolines / Q000494:pharmacology*; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000235:genetics; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D020893:Receptor, ErbB-3 / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D051996:Transcription Factor RelA / Q000378:metabolism; D044648:Undaria / Q000737:chemistry
chemical_list: D000970:Antineoplastic Agents; D066246:ErbB Receptors; D000077341:Lapatinib; D011134:Polysaccharides; D051057:Proto-Oncogene Proteins c-akt; D011799:Quinazolines; D034741:RNA, Small Interfering; D018719:Erb-b2 Receptor Tyrosine Kinases; D020893:Receptor, ErbB-3; D051996:Transcription Factor RelA; C498143:RELA protein, human; C007789:fucoidan; C512478:EGFR protein, human; C508053:ERBB2 protein, human; C581292:ERBB3 protein, human
keywords: ERBB3; fucoidan; lapatinib; melanoma; natural compounds