Cancer is a collection of many different complex diseases that affect our health on a global scale. While treatments exist for many types of cancers, it is well known that in particular chemotherapy can cause significant side-effects. The side effects arise from the chemical compounds used in treatment also being toxic to normal cells in non-cancer tissue, affecting the quality of life of the patients and leading to for example lower immune response which can expose the patients to further infections. Therefore, new and improved strategies for developing chemotherapies that selectively target cancer cells and tumor tissue are needed.
Some of these compounds can come from the natural world, others are synthetic. Melittin, a peptide from honey bee venom, has long been known as an antimicrobial agent, that has also been shown to be effective against several types of cancer cells, from melanoma to pancreatic cancer. Recently it was discovered that it can selectively target aggressive forms of breast cancer over healthy cells, and to lower the resistance of some cancers to conventional chemotherapy agents.
Melittin’s biocidal activity is based on its binding to the lipid membrane surrounding cells. In this project we will use neutron and X-ray methods with computational simulations to unravel the origins of Melittin’s selectivity to cancer cells at the molecular scale. In order to do so, we will develop methods to create deuterium-isotope labelled membranes that mimic cancer and normal tissue. These methods provide a unique insight into structure of cell membranes and how it is altered by Melittin, as well as how Melittin interacts with it.
By creating cell membrane models of cancer and normal cells we can detect how Melittin targets different lipid components, and thereby understand the molecular basis of selectivity. Combining the experimental results with computational simulations, we will obtain a detailed picture of how different lipids influence Melittin’s selectivity and potency against cancer cell membranes, and how engineered forms of Melittin could be made safer for therapies. In doing so, this project will develop new fundamental knowledge that will aid in the design of new and better cancer therapeutics.