Targeting mechanisms of the DNA damage response (DDR) by natural products

Natural products (NP) are important lead substances for the design of new and potent anticancer therapeutics. The common target of approved conventional anticancer drugs is the genomic DNA of tumor cells. If the DNA is damaged, a complex stress response, called DNA damage response (DDR), is activated. The kinases ATM and ATR are the key regulators ensuring the coordinated regulation of DNA repair, activation of cell cycle checkpoints and apoptosis. Therefore, mechanisms of the DDR are attractive target structures for the development of new therapeutic approaches. The aim of the study is to identify NP derived from endophytic fungi, plants, lichens or marine sponges that influence the DDR.

For this purpose, the cytotoxic and DDR modulating potency of 296 natural compounds, used alone or in combination with the cAT cisplatin or doxorubicin was investigated by fluorescence-based analysis of the ATM/ATR-catalyzed S139 phosphorylation of histone 2AX (γH2AX), a surrogate marker of DNA damage. Upon, analyzing DNA double-strand breaks (DSBs), other types of DNA damage and the influence of the NP on the DDR on protein level, a total number of 10 natural products were identified that interfere with the DDR in monotherapy and/or modulate the cAT-stimulated DDR. No interactions with drug transport mechanisms were ascertained.

Based on these results and published data we suggest the NP 5-epi-nakijiquinone Q, 5-epi-ilimaquinone and secalonic acid F as most promising NP-based lead structures for future testing. Mode of action and their anticancer activity in tumor cells of different origin will be determined in forthcoming studies.