Oncotarget

Research Papers:

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

Varsha Thakur, Jun Lu, Giuseppe Roscilli, Luigi Aurisicchio, Manuela Cappelletti, Emiliano Pavoni, William Lindsey White, Barbara Bedogni _

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Oncotarget. 2017; 8:17887-17896. https://doi.org/10.18632/oncotarget.14437

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Abstract

Varsha Thakur1, Jun Lu2, Giuseppe Roscilli3, Luigi Aurisicchio3, Manuela Cappelletti3, Emiliano Pavoni3, William Lindsey White2, Barbara Bedogni1

1Department of Biochemistry, Case Western Reserve University School of Medicine, Cleveland, OH, USA

2School of Science, Auckland University of Technology, New Zealand

3Takis s.r.l., Rome, Italy

Correspondence to:

Barbara Bedogni, email: bxb278@case.edu

Keywords: melanoma, ERBB3, lapatinib, natural compounds, fucoidan

Received: October 04, 2016    Accepted: December 13, 2016    Published: January 02, 2017

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.


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