Marwan K. Al-Shawi, PhD
Mechanism of P-glycoprotein (Drug resistance)
The Al-Shawi laboratory is focused on elucidating the fundamental molecular mechanisms of transmembrane transport processes involving primary energy driven transporters. These investigations have a direct relevance to cancer. Traditional chemotherapeutic agents are quite effective in killing cancer cells until the phenomenon of multidrug resistance is induced in these cells. A primary mechanism by which multidrug resistance arises entails the expression of ABC transporters in the cancer cells of which three ABC-transporters (P-glycoprotein, MRP and MXR) are most relevant to cancer treatment in humans. Additionally, these proteins provide anatomical sanctuaries that are impermeable to chemotherapeutic agents. The main thrust of the work is in performing molecular investigations of the drug transport mechanism of P-glycoprotein. The approach entails the combination of molecular biological studies with rigorous biochemical and biophysical studies and the additional utilization of advanced computational methods. In the last year work continued on: i- Improvements in human P-glycoprotein heterologous expression, purification and mutagenesis in the yeast, Saccharomyces cerevisiae; ii- Molecular dynamics of drug interactions with the membranes; iii- Synthesis of novel spin-labeled transport drugs; iv- P-glycoprotein structural modeling in a physiological membrane; v- Computational molecular dynamics and essential dynamics. The DNA Science and Mass Spectrometry Cores have been helpful in performing these studies. Knowledge acquired from these studies will be used to construct a rigorous, dynamic, molecular description of coupled transport by P-glycoprotein that could aid in the rational design of drugs and methodologies to overcome or modulate this transporter. Such results are expected to be universally applicable to other ABC transport proteins involved in cancer, AIDS and the etiology and treatment of other diseases that involve ABC transporters.