Discovery of chemotherapeutic lead-compounds in cyanobacteri

Cancer is a one of the main causes of death worldwide. There is a sustained need for development of new therapeutics due to poor prognosis and acquired resistance in some hard to treat cancer types, such as those affecting the lung or pancreas. Microorganisms are an extremely valuable source of bioactive compounds with many having clinical applications. The first part of the project focuses on the novel cyanobacterial metabolite, nostatin A, the posterchild compound of this proposal, which affects tumor cell growth and induces tumor cell death. Nostatin A is highly potent against cancer cells of breast and colon origin while sparing primary healthy cells. The second part of the project builds on the previously conducted screening of cyanobacteria-derived compounds from which we obtained a number of promising fractions with potent anticancer activity. The combination of molecular biology, genomics, metabolomics and analytical chemistry in combination with mass spectrometry, will be employed to reveal the molecular mode of action as well as cellular targets of nostatin A and the most potent new substances identified. The acquired knowledge will be essential for future preclinical testing of new anticancer drugs.

Within this project, we collaborated with colleagues in the Czech Republic to identify novel compounds that could serve as future anti-cancer agents. These compounds are derived from a class of very ancient group of bacteria, cyanobacteria, best known for the fact that they were the first producers of oxygen on earth, causing the "Great Oxidation Event". Together, we managed to solve the structure of a lead compound with very potent anti-cancer activity and we identified pathways and molecules involved to kill cancer cells in tissue culture. Moreover, we report how cancer cells respond to this compound by changing gene expression patterns, cell proliferation rates and metabolic activity. Ultimately, cancer cells activate a cellular suicide program, known as apoptosis, when exposed to secondary metabolites from these cyanobacteria. Additional studies are needed though to identify the direct target of these compounds by interaction studies, and pharmacological testing to demonstrate tolerance towards drug-treatment in a living organism.