Abstract
Pro-proliferative oncogenic signaling is one of the hallmarks of cancer. Specific targeting of such signaling pathways is one of the main approaches to modern anti-cancer drug discovery, as opposed to more traditional search for general cytotoxic agents. Natural products, especially from marine sources, represent a largely untapped source of chemical diversity, which so far have mostly been screened for cytotoxicity. Here we present a pioneering pipeline of high-throughput screening of marine-based activities targeted against the Wnt signaling pathway, which is one of the key factors in oncogenic transformation, growth and metastasis in different cancers, including the devastating triple-negative breast cancer (TNBC) currently lacking any targeted therapies. This pipeline consisted of collection and characterization of numerous invertebrates during the SokhoBio expedition to the Kuril Basin in North Pacific, preparation of extracts from these specimen, and their screening in dedicated assays monitoring Wnt signaling in TNBC cells. This approach yielded a number of promising hits, including highly specific anti-Wnt activities targeting multiple levels within the Wnt pathway from Ophiura irrorata and other Pacific brittle stars.
Highlights
Of all marketed drugs, about 40% originate from natural compounds, and this share grows to ca. 50% when looking at small molecule drugs[1]
Ethanol extracts from 81 specimens (Fig. 2 and Supplementary Table S1) were screened at different dilutions, using the triple-negative breast cancer (TNBC) cell line BT-20 stably transfected with the TopFlash reporter construct, which expresses a firefly luciferase under the Wnt-dependent TCF-promoter, so that the luminescence activity of the cells reflects the intensity of Wnt signaling[31], and stimulated by exogenous Wnt3a
Our finding that specimens from three different Ophiura species collected at different locations possess promising activities, inhibiting the Wnt pathway in TNBC cells, hints at the possibility that the same anti-Wnt compound(s) may exist in other brittle stars
Summary
About 40% originate from natural compounds (either directly or through synthetic modifications), and this share grows to ca. 50% when looking at small molecule drugs[1]. Cancer has been the target of extensive screenings of natural products as the potential source of anti-cancer drugs These efforts have resulted in appearance of several anticancer chemotherapeutic agents, such as camptothecines, anthracyclines, taxanes and vinca alcaloids, either originating directly from plants or bacteria or being synthetic derivatives of natural compounds[4]. Development of targeted therapies is the new focus of anti-cancer research of the past decades Such targeted drugs are selective for the cancer cells and have less or (ideally) zero toxicity against healthy tissues. The second subtype relies on over-production of the receptor tyrosine kinase (RTK) HER2 and resulting over-activation of the RTK pathway for excessive cell proliferation; the targeted treatment with anti-HER2 monoclonal antibodies, marketed under the trastuzumab (Herceptin) trade names, is typically applied against this BC subtype[10]
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