Use of adenosine receptor signaling to regulate P-gp function
The present invention relates to a method of inhibiting p-glycoprotein (P-gp) expression in a cell. The method involves contacting a cell expressing P-gp with a composition comprising an effective amount of an A2A adenosine receptor (A2A AR) agonist to inhibit P-gp expression in the cell. Methods of enhancing the bioavailability of a chemotherapeutic in a subject having multi-drug resistant (MDR) cancer and methods of increasing P-gp-mediated efflux in a cell are also disclosed.
1. A method of inhibiting p-glycoprotein (P-gp) expression in a cell, the method comprising:
contacting a cell expressing P-gp with a composition comprising an effective amount of a selective A2A adenosine receptor (A2A AR) agonist to inhibit P-gp expression in the cell, wherein the selective A2A AR agonist is regadenoson, apadenoson, binodenoson, CGS 21680, YT-146, DPMA, PBS 0777 ammonium salt, or A1193; and, wherein said cell expressing P-gp is a cell of the intestine, pancreatic ductules, bile ductules, kidney, adrenal gland; a gonad cell; a breast cell; or a cardiac cell.
2. The method of claim 1 , wherein the cell is of the intestine, pancreatic ductules, bile ductules, kidney, or adrenal gland.
3. The method of claim 1 , wherein the cell is a gonad cell.
4. The method of claim 1 , wherein the cell is a breast cell.
5. The method of claim 4 , wherein the cell also expresses Breast Cancer Resistance Protein 1 (BCRP1) and said contacting is effective to inhibit BCRP1 expression in the cell.
6. The method of claim 1 , wherein the cell is a cardiac cell.
7. The method of claim 1 , wherein the cell is a neoplastic cell.
8. The method of claim 7 , wherein the neoplastic cell has increased P-gp expression, as compared to a non-neoplastic cell.
9. The method of claim 1 , wherein said method is carried out in vivo and further comprises: selecting a subject having a disease or disorder and in need of increased bioavailability of a therapeutic to treat the disease or disorder,
wherein said contacting comprises administering the composition to the selected subject, thereby sensitizing P-gp-expressing cells of the subject to uptake of the therapeutic.
10. The method of claim 9 , wherein the selected subject has a cardiac disease or disorder.
11. The method of claim 9 , wherein the disease or disorder is cancer.
12. The method of claim 11 , wherein the cancer is multi-drug resistant (MDR) cancer.
13. The method of claim 12 , wherein the cancer is within the central nervous system (CNS).
14. The method of claim 9 , wherein said method further comprises:
administering to the selected subject the therapeutic to treat the disease or disorder.
15. The method of claim 14 , wherein the subject has a cardiac disease or disorder and the therapeutic is a digitalis -like compound.
16. The method of claim 14 , wherein the subject is undergoing tissue transplant and the therapeutic is an mTOR inhibitor.
17. The method of claim 14 , wherein the subject has cancer and the therapeutic is a chemotherapeutic.
18. The method of claim 1 , wherein the selective A2A AR agonist is regadenoson.
19. The method of claim 7 , wherein the neoplastic cell is a melanoma cell, a breast cancer cell, an ovarian cancer cell, a prostate cancer cell, a sarcoma cell, a hepatoma cell, a glioma cell, a mesothelioma cell, or a carcinoma cell.