Mechanisms of Betulinic acid‐induced cell death

The scope of this thesis was to investigate the mechanisms by which BetA induces cell death in cancer cells in more detail. At the start of the studies described in this thesis several questions urgently needed an answer. Although BetA induces cell death via apoptosis, when blocking this form of cell death cancer cells still die. In tumor therapy it is still unclear whether activation of autophagy contributes to cell death or rather represents a resistance/survival mechanism. We therefore investigated the roles of other cell death mechanisms including necroptosis and autophagy in BetA‐induced cell death. The results of this investigation are described in chapter 2. BetA induces cell death independently of BAK/BAX but in a mitochondrial dependent fashion, but no reports exist revealing how this form of cell death occurs, we set off to study the mechanism by which BetA induces cell death in more detail. We found that BetA interferes with lipid cell metabolism. The results of this research are described in chapter 3. Cancer stem cells are tumor resistant and currently no effective therapy has been shown for these cells. BetA is a very potent and broad acting compound therefore we treated colon cancer stem cells with BetA. Results of these experiments are laid out in chapter 4. Finally, we were also interested in the effect of BetA on several lipids in the cell. We set‐up a lipidomics pipeline and used a BetA dataset to test the functionality of this pipeline as well as to investigate the difference in lipids after BetA treatment. Chapter 5 contains these results. In chapter 6 all data of this thesis are discussed in relation to the literature.