Methods for overcoming glucocorticoid resistance and for determining glucocorticoid resistance potential in cancer
The invention provides methods for overcoming glucocorticoid resistance of cancers by inhibition of CASP1. Also disclosed are diagnostic methods for determining glucocorticoid resistance potential by measuring expression level or promoter methylation status of CASP1 gene and/or NLRP3 gene.
1. A method of sensitizing a cancer cell to glucocorticoid-induced apoptosis or cell death, wherein said cell is resistant to glucocorticoid-induced apoptosis or cell death and wherein the expression level of CASP1 gene and/or NLRP3 gene in said cell is increased as compared to a corresponding glucocorticoid-sensitive control, comprising contacting the cell with an effective amount of an inhibitor of CASP1.
2. A method of killing a cancer cell, wherein said cell is resistant to glucocorticoid-induced apoptosis or cell death and wherein the expression level of CASP1 gene and/or NLRP3 gene in said cell is increased as compared to a corresponding glucocorticoid-sensitive control, comprising contacting the cell with an amount of an inhibitor of CASP1 that is effective to sensitize the cell to glucocorticoid-induced apoptosis or cell death and further comprising contacting the cell with an effective amount of a glucocorticoid.
3. The method of claim 2 , further comprising contacting the cell with a second agent for inducing apoptosis or cell death.
4. The method of claim 1 , wherein the cancer cell is in a patient.
5. The method of claim 1 , wherein the inhibitor of CASP1 directly inhibits expression or function of CASP1.
6. The method of claim 1 , wherein the inhibitor of CASP1 directly inhibits expression or function of NLRP3.
7. The method of claim 1 , wherein the inhibitor of CASP1 inhibits NLRP3 inflammasome formation or NLRP3 inflammasome activity.
8. The method of claim 1 , wherein the inhibitor of CASP1 is selected from the group consisting of z-VAD-DCB, Ac-YVAD-CHO, Ac-YVAD-chloromethylketone, cytokine response modifier A (crmA), Pralnacasan (VX-740), IDN-6556, VX-765, VRT-043198, ML132, and SNAP.
9. A method of treating a glucocorticoid-resistant cancer in a subject in need thereof, wherein the expression level of CASP1 gene and/or NLRP3 gene in cancer cells of the subject is increased as compared to a corresponding glucocorticoid-sensitive control, which method comprises:
a) (i) determining the expression level of CASP1 gene and/or NLRP3 gene in cancer cells from the subject or (ii) determining the methylation level of CASP1 gene promoter and/or NLRP3 gene promoter in cancer cells from the subject, and
b) administering to the subject (i) a therapeutically effective amount of an inhibitor of CASP1 and (ii) a therapeutically effective amount of a glucocorticoid.
10. The method of claim 9 , wherein the therapeutically effective amount of the inhibitor of CASP1 is an amount that is effective to sensitize cancer cells within the subject to glucocorticoid-induced apoptosis or cell death.
11. The method of claim 5 , wherein the inhibitor of CASP1 is cytokine response modifier A (crmA).
12. The method of claim 1 , wherein the glucocorticoid is prednisolone, dexamethasone, hydrocortisone, prednisone, methylprednisolone, cortisol, or budesonide.
13. The method of claim 1 , wherein the expression level of CASP1 gene and/or NLRP3 gene in said cell is increased by at least 1.5-fold as compared to the corresponding control expression level.
14. The method of claim 2 , wherein the expression level of CASP1 gene and/or NLRP3 gene in said cell is increased by at least 1.5-fold as compared to the corresponding control expression level.
15. The method of claim 9 , wherein the expression level of CASP1 gene and/or NLRP3 gene in said cancer cells is increased by at least 1.5-fold as compared to the corresponding control expression level.
16. A method of treating a glucocorticoid-resistant cancer in a subject in need thereof, wherein the expression level of CASP1 gene and/or NLRP3 gene in cancer cells of the subject is increased as compared to a corresponding glucocorticoid-sensitive control, which method comprises administering to the subject (i) a therapeutically effective amount of an inhibitor of CASP1 and (ii) a therapeutically effective amount of a glucocorticoid.
17. The method of claim 16 , comprising determining the methylation level of CASP1 gene promoter and/or NLRP3 gene promoter in cancer cells from the subject.
18. The method of claim 9 , wherein the cancer is selected from acute lymphoblastic leukemia (ALL), acute myeloblastic leukemia (AML), lymphoma, osteosarcoma, small-cell lung cancer, breast cancer, brain cancer, and multiple myeloma.
19. The method of claim 2 , wherein the cancer cell is in a patient.
20. The method of claim 2 , wherein the inhibitor of CASP1 directly inhibits expression or function of CASP1.
21. The method of claim 2 , wherein the inhibitor of CASP1 directly inhibits expression or function of NLRP3.
22. The method of claim 2 , wherein the inhibitor of CASP1 inhibits NLRP3 inflammasome formation or NLRP3 inflammasome activity.
23. The method of claim 2 , wherein the inhibitor of CASP1 is selected from the group consisting of z-VAD-DCB, Ac-YVAD-CHO, Ac-YVAD-chloromethylketone, cytokine response modifier A (crmA), Pralnacasan (VX-740), IDN-6556, VX-765, VRT-043198, ML132, and SNAP.
24. The method of claim 2 , wherein the glucocorticoid is prednisolone, dexamethasone, hydrocortisone, prednisone, methylprednisolone, cortisol, or budesonide.
25. The method of claim 9 , wherein the inhibitor of CASP1 directly inhibits expression or function of CASP1.
26. The method of claim 9 , wherein the inhibitor of CASP1 directly inhibits expression or function of NLRP3.
27. The method of claim 9 , wherein the inhibitor of CASP1 inhibits NLRP3 inflammasome formation or NLRP3 inflammasome activity.
28. The method of claim 9 , wherein the inhibitor of CASP1 is selected from the group consisting of z-VAD-DCB, Ac-YVAD-CHO, Ac-YVAD-chloromethylketone, cytokine response modifier A (crmA), Pralnacasan (VX-740), IDN-6556, VX-765, VRT-043198, ML132, and SNAP.
29. The method of claim 9 , wherein the glucocorticoid is prednisolone, dexamethasone, hydrocortisone, prednisone, methylprednisolone, cortisol, or budesonide.
30. The method of claim 16 , comprising determining the expression level of CASP1 gene and/or NLRP3 gene in cancer cells from the subject.
31. The method of claim 16 , wherein the cancer is selected from acute lymphoblastic leukemia (ALL), acute myeloblastic leukemia (AML), lymphoma, osteosarcoma, small-cell lung cancer, breast cancer, brain cancer, and multiple myeloma.
32. The method of claim 16 , wherein the inhibitor of CASP1 directly inhibits expression or function of CASP1.
33. The method of claim 16 , wherein the inhibitor of CASP1 directly inhibits expression or function of NLRP3.
34. The method of claim 16 , wherein the inhibitor of CASP1 inhibits NLRP3 inflammasome formation or NLRP3 inflammasome activity.
35. The method of claim 16 , wherein the inhibitor of CASP1 is selected from the group consisting of z-VAD-DCB, Ac-YVAD-CHO, Ac-YVAD-chloromethylketone, cytokine response modifier A (crmA), Pralnacasan (VX-740), IDN-6556, VX-765, VRT-043198, ML132, and SNAP.
36. The method of claim 16 , wherein the glucocorticoid is prednisolone, dexamethasone, hydrocortisone, prednisone, methylprednisolone, cortisol, or budesonide.
37. The method of claim 16 , wherein the expression level of CASP1 gene and/or NLRP3 gene in said cancer cells is increased by at least 1.5-fold as compared to the corresponding control expression level.
38. The method of claim 16 , wherein the therapeutically effective amount of the inhibitor of CASP1 is an amount that is effective to sensitize cancer cells within the subject to glucocorticoid-induced apoptosis or cell death.