Use of phosphodiesterase inhibitors for treating multidrug resistance
The present invention relates to methods of treating multidrug resistance in cancerous cells with phosphodiesterase (PDE) inhibitors, e.g., PDE5 inhibitors. More specifically, the invention relates to methods of treating multidrug resistance that arises, e.g., during administration of chemotherapeutic/antineoplastic (anticancer) agents for treatment of cancer, with a PDE5 inhibitor (e.g., sildenafil, vardenafil, and tadalafil). The invention also relates to methods of treating cancer, e.g., multidrug resistant cancer, using a PDE5 inhibitor in combination with an antineoplastic therapeutic agent. Further, the invention relates to pharmaceutical compositions for treating multidrug resistant cancers comprising a PDE5 inhibitor, or a combination of a PDE5 inhibitor and an antineoplastic agent.
1. A method of treating multidrug resistance in a cancer cell in a subject in need thereof by inhibiting ABCB1 transporter activity, comprising administering to the subject a therapeutically effective amount of a phosphodiesterase 5 (PDE5) inhibitor.
2. The method of claim 1 , wherein the PDE5 inhibitor is selected from the group consisting of sildenafil, vardenafil, tadalafil, lodenafil, udenafil, benzamidenafil, mirodenafil, avanafil, zaprinast, SLX-2101, UK-371,800, UK-122764, icariin, DA-8159, and 3-[4-(2-hydroxyethyl)piperazin-1-yl]-7-(6-methoxypyridin-3-yl)-1-(2-propoxyethyl)pyrido[3,4-b]-pyrazin-2(1H)-one.
3. The method of claim 2 , wherein the PDE5 inhibitor is sildenafil.
4. The method of claim 2 , wherein the PDE5 inhibitor is vardenafil.
5. The method of claim 2 , wherein the PDE5 inhibitor is tadalafil.
6. The method of claim 1 , wherein the PDE5 inhibitor is administered in combination with an antineoplastic agent.
7. The method of claim 6 , wherein the antineoplastic agent is selected from the group consisting of antineoplastic agents listed in Table 1.
8. The method of claim 7 , wherein the antineoplastic agent is selected from the group consisting of paclitaxel, vinblastine, and vincristine.
9. A method of treating multidrug resistance in a cancer cell in a subject in need thereof by inhibiting ABCG2 transporter activity, comprising administering to the subject a therapeutically effective amount of a PDE5 inhibitor.
10. The method of claim 9 , wherein the PDE5 inhibitor is selected from the group consisting of sildenafil, lodenafil, udenafil, benzamidenafil, mirodenafil, avanafil, zaprinast, SLX-2101, UK-371,800, UK-122764, icariin, DA-8159, and 3-[4-(2-hydroxyethyl)piperazin-1-yl]-7-(6-methoxypyridin-3-yl)-1-(2-propoxyethyl)pyrido[3,4-b]-pyrazin-2(1H)-one.
11. The method of claim 10 , wherein the PDE5 inhibitor is sildenafil.
12. The method of claim 9 , wherein the PDE5 inhibitor is administered in combination with an antineoplastic agent.
13. The method of claim 12 , wherein the antineoplastic agent is selected from the group consisting of antineoplastic agents listed in Table 2.
14. The method of claim 13 , wherein the antineoplastic agent is selected from the group consisting of SN-38, flavopiridol, mitoxantrone, and methotrexate.
15. A method of treating multidrug resistance in a cancer cell in a subject in need thereof by inhibiting ABCC10 transporter activity, comprising administering to the subject a therapeutically effective amount of a PDE5 inhibitor.
16. The method of claim 15 , wherein the PDE5 inhibitor is selected from the group consisting of sildenafil, vardenafil, tadalafil, lodenafil, udenafil, benzamidenafil, mirodenafil, avanafil, zaprinast, SLX-2101, UK-371,800, UK-122764, icariin, DA-8159, and 3-[4-(2-hydroxyethyl)piperazin-1-yl]7-(6-methoxypyridin-3-yl)-1-(2-propoxyethyl)pyrido[3,4-b]-pyrazin-2(1H)-one.
17. The method of claim 16 , wherein the PDE5 inhibitor is sildenafil.
18. The method of claim 16 , wherein the PDE5 inhibitor is vardenafil.
19. The method of claim 15 , wherein the PDE5 inhibitor is administered in combination with an antineoplastic agent.
20. The method of claim 19 , wherein the antineoplastic agent is selected from the group consisting of antineoplastic agents listed in Table 3.
21. The method of claim 20 , wherein the antineoplastic agent is selected from the group consisting of paclitaxel, docetaxel, vinblastine, and vincristine.