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Benzophenone Compounds, from a Marine-Derived Strain of the Fungus Pestalotiopsis neglecta, Inhibit Proliferation of Pancreatic Cancer Cells by Targeting the MEK/ERK Pathway
journal contribution
posted on 2019-12-12, 13:50 authored by Weihong Wang, Chanyoon Park, Eunseok Oh, Youjung Sung, Jusung Lee, Kyu-Hyung Park, Heonjoong KangPancreatic cancer, which has an extremely poor prognosis,
is one
of the most fatal human cancers. Chemotherapy is the main palliative
treatment for advanced cancer patients and also plays an indispensable
role in postoperative treatments for surgical patients. Therefore,
there is an urgent need to develop more innovative anticancer drugs
to fight against this fatal disease. Here, we investigate the potential
of benzophenone derivatives, obtained from a marine-derived strain
of the fungus Pestalotiopsis neglecta, as antiproliferative
lead compounds for the treatment of pancreatic cancer. The compounds,
seven new (1–7) and two known (8 and 9) halogenated benzophenone derivatives,
were obtained by bioactivity-guided fractionation from the cultures
of Pestalotiopsis neglecta. The structures were defined
by spectroscopic methods including X-ray crystallographic analysis.
Using the commonly used pancreatic cancer cell line PANC-1, 2 and 4 were found to suppress cell proliferation
and induce apoptosis in the low micromolar range of 7.6 and 7.2 μM,
respectively. Mechanistically, benzophenone derivatives not only inhibit
MEK activity in the cytoplasm but also suppress ERK activity in the
cytoplasm and nucleus. An in silico study suggests
that benzophenone derivatives could potentially inhibit MEK activity
by binding to the allosteric pocket in MEK. Benzophenones could serve
as new lead compounds for the treatment of pancreatic cancer.