15-PGDH in colon cancer
The disclosure provides, among other things, a method of decreasing resistance to the chemopreventive properties of non-steroidal anti-inflammatory agents, e.g., celecoxib, particularly in the prevention of cancer, e.g., colon cancer, by increasing the levels or activity of 15-hydroxyprostaglandin dehydrogenase (15-PGDH). The disclosure also provides a method of identifying compounds that upregulate or reactivate 15-PGDH. The disclosure also provides a method of identifying an individual suitable for treatment with a non-steroidal anti-inflammatory agent in the treatment or prevention of colon cancer.
1. A method of treating a non-steroidal anti-inflammatory drug (NSAID)-responsive condition in a human subject, wherein the NSAID-responsive condition is selected from the group consisting of: an inflammatory disorder, an immunologic disorder, and colon neoplasia, and wherein the subject has been determined to have increased or decreased levels of 15-hydroxyprostaglandin dehydrogenase (15-PGDH), the method comprising:
(i) administering to the subject an effective amount of an NSAID if the levels of 15-PGDH are increased; or
(ii) administering to the subject an effective amount of an NSAID and an agent that upregulates 15-PGDH, wherein the agent is not a Prox-1 suppressor, if the levels of 15-PGDH are decreased.
2. The method according to claim 1 , wherein the NSAID-responsive condition is colon neoplasia.
3. The method according to claim 2 , wherein the colon neoplasia is colon cancer.
4. The method according to claim 2 , wherein the colon neoplasia is colon adenoma.
5. The method according to claim 1 , wherein the NSAID-responsive condition is an inflammatory disorder or an immunologic disorder.
6. The method according to claim 1 , wherein the NSAID is celecoxib or aspirin.
7. The method according to claim 1 , wherein the agent is selected from the group consisting of: a small molecule, a polypeptide, nucleic acid, aptamers, and antibody.
8. The method according to claim 7 , wherein the small molecule is erlotinib or butyrate.
9. The method according to claim 7 , wherein the nucleic acid is an siRNA or antisense.
10. The method according to claim 9 , wherein the siRNA inhibits the expression of beta-catenin transcription factor.
11. The method according to claim 1 , wherein the agent directly or indirectly upregulates 15-PGDH levels or activity.
12. A method of decreasing non-steroidal anti-inflammatory drug (NSAID) resistance in a human subject, wherein the subject has an NSAID-responsive condition selected from the group consisting of: an inflammatory disorder, an immunologic disorder, and colon neoplasia, and wherein the subject has been determined to have decreased levels of 15-hydroxyprostaglandin dehydrogenase (15-PGDH), the method comprising administering to the subject:
(i) an effective amount of a compound that increases 15-PGDH levels or 15-PGDH activity; or
(ii) an effective amount of 15-PGDH protein, cDNA, or an active fragment thereof, wherein a compound that increases 15-PGDH levels is not a Prox-1 suppressor.
13. The method according to claim 12 , wherein the 15-PGDH levels include protein, mRNA, or cDNA level of 15-PGDH.
14. The method according to claim 12 , wherein the compound is selected from the group consisting of: a small molecule, a polypeptide, a nucleic acid, an aptamer, and an antibody.
15. The method according to claim 14 , wherein the nucleic acid is an siRNA or antisense.
16. The method according to claim 15 , wherein the siRNA inhibits the expression of beta-catenin transcription factor.
17. The method according to claim 12 , wherein the compound directly or indirectly upregulates 15-PGDH levels or activity.
18. A method of treating a non-steroidal anti-inflammatory drug (NSAID)-responsive condition in a human subject, wherein the NSAID-responsive condition is colon neoplasia, and wherein the subject has been determined to have decreased levels of 15-hydroxyprostaglandin dehydrogenase (15-PGDH), the method comprising administering to the subject an effective amount of an NSAID and an agent that upregulates 15-PGDH.
19. The method of claim 18 , wherein the agent is erlotinib or butyrate.
20. A method of treating a non-steroidal anti-inflammatory drug (NSAID)-responsive condition in a human subject, wherein the NSAID-responsive condition is colon neoplasia, and wherein the subject has been determined to have increased levels of 15-hydroxyprostaglandin dehydrogenase (15-PGDH), the method comprising administering to the subject an effective amount of an NSAID.
21. The method according to any of claims 18 - 20 , wherein the NSAID is celecoxib or aspirin.