Improving rescinnamine as an inducer of MSH2-dependent apoptosis in cancer treatment
Karin Drotschmann Scarpinato, Elshimaa M. N. Abdelhafez, Andrew Diamanduros, Lacramioara Negureanu, Yan Lü, Bean Jh, Katherine Zielke, Brittany Crowe, Aksana Vasilyeva, Jill E. Clodfelter, Omar M. Aly, Gamal El‐Din A. Abuo‐Rahma, Freddie R. Salsbury, Stephen B. King · WakeSpace Scholarship (Wake Forest University) · 2013
We, and others have previously shown that mismatch repair proteins, in addition to their repair function, have the ability to contribute to cell death initiation. In response to some drugs, this cell death activity is independent of the repair function of the proteins. Rescinnamine, a derivative of the indole alkaloid reserpine, a drug used to treat hypertension several decades ago, was shown to target the cell death-initiating activity of mismatch repair proteins. When used in animals, the hypotensive action of this drug prevents applying appropriate concentrations for statistically significant tumor reduction. Here we used a combination of computational modeling, chemical synthesis and cell assays to determine how rescinnamine can be modified and what effect these modifications have on cell survival. Results inform further computational modeling to suggest new lead molecules to move toward further testing.