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Identification of immunological properties of natural products for the treatment of resistant tumors and bacterial pathogens

Richter, L;

Both cancer and diseases caused by bacterial infections are among the most common
causes of death worldwide. Due to increasing population numbers and a higher life
expectancy, incidence rates are expected to grow. Treatment gets even more
challenging due to the existence and continuous development of resistances against
established therapies. Alternative approaches are provided by immunotherapy which
aims at the direct targeting of immune functions. Promising targets for immunotherapy
are antigen-presenting cells which are key for the induction of effective adaptive immune
An auspicious source of novel compounds suitable for drug development is represented
by natural products. Natural products comprise a great variety of highly bioactive
molecules produced by various organisms as adaption to biotic and abiotic stress factors
and have already inspired drug development. Furthermore, histone deacetylase
inhibitors are derivatives of natural products and exhibit advantageous features
especially for anti-cancer treatment.
Due to the lack of appropriate screening guidelines for the definition of immune activating
properties of natural products and their suitability for immunotherapeutic application, new
guidelines have been established under the comprehensive application of different
mouse models and are described in this thesis. Following this, natural products should
be non-toxic to immune target cells, exhibit beneficial direct activities against cancer cells
or pathogens and promote immune activation. 240 natural products derived from
endophytic fungi and marine sponges have been analyzed accordingly. Three
compounds have been found to be promising for further drug development accompanied
by potential biochemical optimization. Additionally, two histone deacetylase inhibitors
with preferences for histone deacetylase 6 or histone deacetylases 6 and 1 have been
identified to enhance type I interferon production by plasmacytoid dendritic cells at
simultaneous stimulation with the double-stranded RNA analog poly I:C. Promising,
optimized natural products and histone deacetylase inhibitors might be administered in
in vivo tumor and infection mouse models and analyzed in clinical trials.
In summary, the experiments and guidelines presented in this thesis aim at the
identification of compounds that simultaneously (re-) activate immune cells and target
tumors and bacteria thus helping to overcome resistance mechanisms.