Combination Therapy with Triterpenoid Compounds and Proteasome Inhibitors

• US 20090018146A1
• Filed: 01/26/2006
• Published: 01/15/2009
• Est. Priority Date: 01/27/2005
• Status: Abandoned Application

• Current Assignee: Research & Development Foundation
• Original Assignee: UAB Research Foundation (University of Alabama System)
• Inventors: Poblenz, Ann, Gaikwad, Amos, Haridas, Valsala, Gutterman, Jordan
• Application Number:
  US11/814,268
• Publication Number:
  US 20090018146A1
• Time in Patent Office: Days
• US Class Current: 514/255.60
• CPC Class Codes: A61K 2300/00 Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
• CPC Class Codes: A61K 31/69 Boron compounds
• CPC Class Codes: A61K 36/48 Fabaceae or Leguminosae (Pea or Legume family); Caesalpiniaceae; Mimosaceae; Papilionaceae
• CPC Class Codes: A61K 38/02 Peptides of undefined number of amino acids; Derivatives thereof
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61P 29/00 Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• CPC Class Codes: A61P 35/00 Antineoplastic agents

Abstract

The present invention provides therapeutic compositions comprising a natural triterpenoid and a proteasome inhibitor. These compositions will be particularly useful in the treatment of malignancies and inflammation. The present invention also provides methods of treating a subject having a malignancy or an inflammatory disorder comprising administering to the subject a natural triterpenoid and a proteasome inhibitor.

Claims

1. A method of inducing apoptosis in a malignant cell comprising contacting the malignant cell with a natural triterpenoid and a proteasome inhibitor.

2. The method of claim 1, wherein the natural triterpenoid is a plant-derived triterpenoid.

3. The method of claim 2, wherein the plant-derived triterpenoid is derivable from a plant of the Acacia genus.

4. The method of claim 3, wherein the plant-derived triterpenoid is derivable from Acacia victoriae.

5. The method of claim 1, wherein the natural triterpenoid is an avicin.

6. The method of claim 1, wherein the proteasome inhibitor is a peptide aldehyde, a peptide boronate, a peptide vinyl sulfone, a peptide epoxyketone, a lactacystin, or a lactacystin derivative.

7. The method of claim 1, wherein the malignant cell is a cancer cell.

8. The method of claim 7, wherein the cancer cell is an ovarian cancer cell, a pancreatic cancer cell, a renal cancer cell, a prostate cancer cell, a melanoma cell, or a leukemia cell.

47. The method of claim 7 wherein the cancer cell is a multiple myeloma cell.

9. A method treating a subject with a malignancy comprising administering to said subject a natural triterpenoid and a proteasome inhibitor.

10. The method of claim 9, wherein the subject is a mammal.

11. The method of claim 10, wherein the mammal is a human.

12. The method of claim 9, wherein said administering is via a route selected from the group consisting of intratumoral injection, intravenous injection, oral, and topical.

13. The method of claim 9, wherein the natural triterpenoid is a plant-derived triterpenoid.

14. The method of claim 13, wherein the plant-derived triterpenoid is derivable from a plant of the Acacia genus.

15. The method of claim 14, wherein the plant-derived triterpenoid is derivable from Acacia victoriae.

16. The method of claim 9, wherein the natural triterpenoid is an avicin.

17. The method of claim 9, wherein the proteasome inhibitor is a peptide aldehyde, a peptide boronate, a peptide vinyl sulfone, a peptide epoxyketone, a lactacystin, or a lactacystin derivative.

18. A method treating a subject with an inflammatory disorder comprising administering to said subject a natural triterpenoid and a proteasome inhibitor.

19. The method of claim 18, wherein the subject is a mammal.

20. The method of claim 19, wherein the mammal is a human.

21. The method of claim 18, wherein said administering is via a route selected from the group consisting of intratumoral injection, intravenous injection, oral, and topical.

22. The method of claim 18, wherein the natural triterpenoid is a plant-derived triterpenoid.

23. The method of claim 22, wherein the plant-derived triterpenoid is derivable from a plant of the Acacia genus.

24. The method of claim 23, wherein the plant-derived triterpenoid is derivable from Acacia victoriae.

25. The method of claim 18, wherein the natural triterpenoid is an avicin.

26. The method of claim 18, wherein the proteasome inhibitor is a peptide aldehyde, a peptide boronate, a peptide vinyl sulfone, a peptide epoxyketone, a lactacystin, or a lactacystin derivative.

27. The method of claim 18, wherein the inflammatory disorder is an autoimmune disorder.

28. A pharmaceutical composition comprising a natural triterpenoid and a proteasome inhibitor in a pharmacologically acceptable buffer, solvent or diluent.

29. The pharmaceutical composition of claim 28, wherein the natural triterpenoid is further defined as Avicin D and the proteasome inhibitor is further defined as PS-341 (bortezomib).

30. The pharmaceutical composition of claim 28, wherein the natural triterpenoid is further defined as Avicin G and the proteasome inhibitor is further defined as PS-341 (bortezomib).

31. The pharmaceutical composition of claim 28, wherein the natural triterpenoid is further defined as Avicin B and the proteasome inhibitor is further defined as PS-341 (bortezomib).

32. A method of treating cell proliferative disease in a subject comprising, administering an effective amount of a natural triterpenoid compound and an effective amount of a proteasome inhibitor.

33. The method of claim 32, wherein the natural triterpenoid compound and the proteasome inhibitor are administered simultaneously.

34. The method of claim 32, wherein the natural triterpenoid compound and the proteasome inhibitor are administered sequentially.

35. The method of claim 32, wherein the cell proliferative disease is a cancer.

36. The method of claim 35, wherein in the cancer is an ovarian cancer, a pancreatic cancer, a renal cancer, a prostate cancer, a melanoma, or a leukemia.

37. The method of claim 35, wherein the cancer is multiple myeloma.

38. The method of claim 32, wherein the natural triterpenoid is a plant-derived triterpenoid.

39. The method of claim 38, wherein the plant-derived triterpenoid is derivable from a plant of the Acacia genus.

40. The method of claim 39, wherein the plant-derived triterpenoid is derivable from Acacia victoriae.

41. The method of claim 32, wherein the natural triterpenoid is an avicin.

42. The method of claims 41, wherein the avicin is Avicin B, Avacin G or Avacin D.

43. The method of claim 32, wherein the proteasome inhibitor is a peptide aldehyde, a peptide boronate, a peptide vinyl sulfone, a peptide epoxyketone, a lactacystin, or a lactacystin derivative.

44. The method of claim, 43 wherein the proteasome inhibitor is PS341 (bortezomib).

45. The method of claim 37, wherein the proteasome inhibitor is PS341 (bortezomib) and the natural triterpenoid is an avicin.

46. The method of claims 45, wherein the avicin is Avicin B, Avicin G or Avicin D.