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Abstract
A key condition for the efficacy of chemotherapy is that it reaches the tumor mass at a therapeutic concentration. In CNS tumors this process is hampered by the blood brain barrier (BBB). Lately emerged that Multi Drug Resistance (MDR) phenomenon is explained through the cooperation of P-glycoprotein (P-gp) and Breast Cancer Resistance Protein (BCRP), two “gatekeeper” efflux pumps working in tandem on the BBB, also present on plasma-membrane of certain brain tumors. Recently, we have demonstrated that morphine, ondansetron and dexamethasone can interfere with the permeability of BBB allowing doxorubicine accumulation within the rat brain, detected by LC-MS/MS mass spectrometry. All these drugs are substrates of P-gp and BCRP transporters. The aim of the current proposal is to understand the action mechanism of BBB “permeabilization” induced by morphine or other drugs and to exploit this method for the “treatment” of brain tumor in an animal model; i) Quantifying the level drugs that do not usually cross the BBB (mitoxantrone or melphalan) after morphine pre-treatment in a preclinical model. Verifying the cytotoxic effect of morphine plus doxorubicin (and other chemotherapeutic agents) treatment by using MTT and TUNEL analysis in glioblastoma cell lines; ii) Quantifying the level of drugs that do not usually cross the BBB after morphine pre-treatment in an artificial BBB through a monolayer of MDCKII cells over-expressing the human P-gp or BCRP; iii) Investigating the regulatory role of certain microRNA in MDR mechanism by RT-PCR and western blot analysis of P-gp, BCRP, miR-21, miR-27a and miR-451. Our preliminary results suggest that blocking efflux transporters by pretreatment with morphine, ondansetron or desamethasone is able to allow doxorubicin penetration inside the brain. These data will enable us to novel therapeutic approaches to refractory or recurrent CNS tumors in which molecules usually stopped by the BBB may have a therapeutic impact.
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