Materials and methods for treatment of cancer and identification of anti-cancer compounds
The subject invention pertains to the treatment of tumors and cancerous tissues and the prevention of tumorigenesis and malignant transformation through the modulation of JAK/STAT3 intracellular signaling. The subject invention concerns pharmaceutical compositions containing cucurbitacin I, or a pharmaceutically acceptable salt or analog thereof, to a patient, wherein the tumor is characterized by the constitutive activation of the JAK/STAT3 intracellular signaling pathway. The present invention further pertains to methods of moderating the JAK and/or STAT3 signaling pathways in vitro or in vivo using cucurbitacin I, or a pharmaceutically acceptable salt or analog therof. Another aspect of the present invention concerns a method for screening candidate compounds for JAK AND/or STAT3 inhibition and anti-tumor activity.
1. A method for inhibiting the growth of a cancer that is characterized by constitutive activation of the STAT3 signaling pathway and/or abnormally elevated levels of tyrosine phosphorylated STAT3, said method comprising administering an effective amount of cucurbitacin I, or a pharmaceutically acceptable salt or analog thereof, to a patient in need of such treatment, wherein said cucurbitacin I, or said pharmaceutically acceptable salt or analog thereof, inhibits said STAT3 signaling pathway and reduces the levels of said tyrosine phosphorylated STAT3 in a cell of said cancer.
2. The method according to claim 1 , wherein the analog is a compound of structure I, or a pharmaceutically acceptable salt thereof:
wherein R 1 , R 2 , R 3 , R 4 , R 5 , and R 6 can each be the same or different, and are each selected from the group consisting of H, O, hydroxyl, alkyl, alkenyl, alkynyl, halogen, alkoxy, aryl and heteroaryl.
3. The method according to claim 1 , wherein the cucurbitacin I, or a pharmaceutically acceptable salt or analog thereof, inhibits the STAT3 signaling pathway and/or suppression of abnormally elevated levels of tyrosine phosphorylated STAT3.
4. The method according to claim 1 , wherein the analog inhibits the STAT3 signaling pathway, but does not inhibit the JAK2 signaling pathway.
5. The method according to claim 1 , wherein the patient is suffering from a tumor and the growth of the tumor is inhibited or cell death is induced in the tumor by the cucurbitacin I, or a pharmaceutically acceptable salt or analog thereof.
6. The method according to claim 1 , wherein the cancer is selected from the group consisting of pancreatic cancer, prostate cancer, and breast cancer.
7. The method according to claim 1 , wherein cucurbitacin I, or a pharmaceutically acceptable salt thereof, is administered to the patient.
8. The method according to claim 1 , wherein the route of said administration is selected from the group consisting of intravenous, intramuscular, oral, and intra-nasal.
9. The method of claim 1 , wherein the cancer is non-small cell lung cancer.
10. The method of claim 1 , further comprising the step of testing the cancer of the patient to determine if the cancer is characterized by constitutive activation of the STAT3 signaling pathway and/or abnormally elevated levels of tyrosine phosphorylated STAT3.
11. The method of claim 1 , wherein cell death is induced in the cancer by the cucurbitacin I, or a pharmaceutically acceptable salt or analog thereof.
12. The method according to claim 1 , wherein the analog is cucurbitacin A.
13. The method according to claim 1 , wherein the analog is cucurbitacin B.
14. The method according to claim 1 , wherein the analog is cucurbitacin D.
15. The method according to claim 1 , wherein the analog is cucurbitacin E.
16. The method according to claim 1 , wherein the analog is tetrahydro-cucurbitacin I.
17. The method according to claim 1 , wherein the cancer is pancreatic cancer.
18. The method according to claim 1 , wherein the cancer is breast cancer.