Abstract
The blood-brain barrier is a primary obstacle for effective anticancer drug therapy of patients with glioblastoma multiforme (GBM). On a molecular level, failure of anticancer drug treatment is largely due to the blood-brain barrier efflux transporters P-glycoprotein (P-gp) and Breast Cancer Resistance Protein (BCRP). P-gp and BCRP (P-gp/BCRP) work together to restrict anticancer drugs from crossing the barrier and from entering the brain to reach tumor targets. We found that PI3K/Akt regulates P-gp/BCRP in brain capillaries of the rodent and human blood-brain barrier. Our in vivo data show that combination treatment with LY294002 (PI3K inhibitor) and triciribine (Akt inhibitor) downregulates P-gp and BCRP protein expression and transport activity in brain capillaries. We also have evidence from brain capillaries isolated from GBM mice and GBM patients showing that GBM induces P-gp/BCRP overexpression in capillaries in the brain hemisphere that is contralateral to the primary tumor. These findings indicate that P-gp/BCRP overexpression in brain capillaries protects invasive tumor cells that are scattered throughout the brain from being targeted by anticancer drugs. To overcome this obstacle, we are currently developing a novel therapeutic strategy by targeting PI3K/Akt to transiently decrease P-gp/BCRP expression and activity, thus, creating a “window-in-time” during which anticancer drugs can enter the brain.