Planta Medica International Open 2017; 4(S 01): S1-S202
DOI: 10.1055/s-0037-1608163
Poster Session
Georg Thieme Verlag KG Stuttgart · New York

Looking for specific natural inhibitors targeting aberrant proliferation signaling in melanoma

E Garo
1   Department of Pharmaceutical Sciences, University of Basel, Basel, Switzerland
,
M Dobrzyński
2   Institute of Cell Biology, University of Bern, Bern, Switzerland
,
F Rossberg
1   Department of Pharmaceutical Sciences, University of Basel, Basel, Switzerland
,
O Fertig
1   Department of Pharmaceutical Sciences, University of Basel, Basel, Switzerland
,
O Pertz
2   Institute of Cell Biology, University of Bern, Bern, Switzerland
,
M Hamburger
1   Department of Pharmaceutical Sciences, University of Basel, Basel, Switzerland
› Author Affiliations
Further Information

Publication History

Publication Date:
24 October 2017 (online)

 

The incidence of melanoma, the most fatal dermatological cancer, is dramatically rising. In more than 50% of malignant melanomas the BRAF V600E mutation is present, leading to aberrant MAPK signaling and uncontrolled proliferation. Vemurafenib, a specific inhibitor of the V600E mutated form of B-Raf, has been approved in 2011 for the treatment of metastatic melanomas. Despite spectacular initial results, patients treated with vemurafenib relapse within 2 – 18 months due to drug resistance. Studies on the mechanism of drug resistance suggest that the development of combination therapies is needed to address this problem. Novel inhibitors targeting aberrant proliferation signaling (MAPK and PI3K pathways) in melanoma are therefore urgently needed.

To identify novel compounds for targeted therapy we combined our natural product lead discovery platform with an innovative high-content screening (HCS) assay that quantifies MAPK/PI3K signaling in A2058 melanoma cells. The HCS assay was first validated with known specific inhibitors, prior to its use for an initial screening of 88 plant extracts. An EtOAc extract from leaves of Casearia arborea was found to inhibit both the MAPK and PI3K pathways in A2058 cells. HPLC-based activity profiling combined with an efficient dereplication strategy identified Cucurbitacins Q (1) and B (2) to be responsible for the activity in the extract. These results were obtained in analytical scale using less than 5 mg of extract. A scale-up isolation will allow for the full structural assignment of the compounds, and for further characterization of mechanisms of action. The current results provide a proof of concept for our approach that is now used for the screening and profiling of a library of > 800 EtOAc extracts.