In cancer treatment, one of the primary goals is to preferentially destroy cancerous cells without extensively damaging normal tissue. Current efforts are focused on identifying unique cellular defects that can be specifically targeted to achieve this goal. P27kip1 (p27) is a tumor suppressor protein commonly deregulated in aggressive cancers. The Sheaff lab recently discovered that p27 deregulation provides cancer cells with a growth advantage by altering nutrient metabolic pathways. In early stages of tumor development, cancer cells lack a steady blood supply and hence a steady supply of glucose. Under these condition, we found that cells without p27 can switch to amino acids as a carbon source, allowing the tumor to continue growing. This switch can also be observed by treating p27-/- cells with the glucose analog 2 deoxy-glucose (2DG), which activates a switch to amino acids. This pathway can then be targeted with rotenone, a well-known inhibitor of complex 1 of the electron transport chain. This drug combination can be used to specifically target cells lacking p27, and hence could potentially develop into a novel therapeutic approach for these type of aggressive cancers. However, rotenone is extremely toxic to humans, so our goal was to identify a different metabolic inhibitor selectively targeting p27-/- cells in conjunction with 2DG. Our approach was to modify various amino acids with reducing sugars via the Maillard reaction, then evaluate their ability to specifically target p27-/- cells. Purified amino acids and different reducing sugars were mixed and autoclaved to drive the Maillard reaction. Resulting solutions were analyzed for their ability to specifically target ATP production and decrease the viability of p27-/- cells. Wild type cells containing p27 served as the control. Results indicate that products generated in the Maillard reaction may specifically target cells lacking p27, and thus represent a potential novel source of therapeutic agents.

Development of novel chemotherapeutic agents via the Maillard reaction

255th National Meeting (2018)

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