1 / 27

Redox NSAIDs and VEGF Terry Moody, Ph.D. NCI Center for Cancer Research Bldg. 31, Rm. 4A48 301-451-9451 moodyt@mail.nih.

Redox NSAIDs and VEGF Terry Moody, Ph.D. NCI Center for Cancer Research Bldg. 31, Rm. 4A48 301-451-9451 moodyt@mail.nih.gov. Lung Cancer kills over 150,000 patients in the U.S. annually. There are 45 Million current smokers and 45 Million ex-smokers in the U.S.

tod
Download Presentation

Redox NSAIDs and VEGF Terry Moody, Ph.D. NCI Center for Cancer Research Bldg. 31, Rm. 4A48 301-451-9451 moodyt@mail.nih.

An Image/Link below is provided (as is) to download presentation Download Policy: Content on the Website is provided to you AS IS for your information and personal use and may not be sold / licensed / shared on other websites without getting consent from its author. Content is provided to you AS IS for your information and personal use only. Download presentation by click this link. While downloading, if for some reason you are not able to download a presentation, the publisher may have deleted the file from their server. During download, if you can't get a presentation, the file might be deleted by the publisher.

E N D

Presentation Transcript

  1. Redox NSAIDs and VEGF Terry Moody, Ph.D. NCI Center for Cancer Research Bldg. 31, Rm. 4A48 301-451-9451 moodyt@mail.nih.gov

  2. Lung Cancer kills over 150,000 patients in the U.S. annually. • There are 45 Million current smokers and 45 Million ex-smokers in the U.S. • Lung cancer is comprised of the neuroendocrine tumor small cell lung cancer (SCLC) and the epithelial tumor non-small cell lung cancer (NSCLC) • NSCLC is associated with elevated levels of COX-2

  3. Indomethacin, which blocks COX-1 and COX-2, prevents lung adenoma formation in A/J mice.

  4. The A/J mouse develops lung adenomas after carcinogen administration.

  5. COX-2 immunostaining inthe A/J mouse lung.

  6. Lung compartments and COX-2. • Bronchus-epithelial cells show intense staining with moderate staining in the muscle but not cartilage. • Bronchioles-Moderate staining in epithelial cells. • Alveoli-Moderate staining in type 2 cells. • Adenoma-scattered cellular staining.

  7. S-NSAIDs and cancer cells ●Effects on PGE2 ●Effects on proliferation

  8. COX-1 is expressed in lung cancer cells. Hida et al., (1998); Anticancer Res. 18:775.

  9. EGF causes increases COX-2 expression in NSCLC cells.

  10. Novel NSAIDs reduce PGE2 in colon cancer cells. Addition PGE2, pg None 90 Asp-NO, 1 ug/ml 16 ACS2, 1 ug/ml 24 ACS15, 1 ug/ml 16 ACS18, 1 ug/ml 58 The mean value of 4 determinations is indicated using supernatant from HT-29 cells incubated with 20 uM arachidonic acid for 5 min by ELISA.

  11. S-NSAIDs and COX-2 inhibitors reduce HT-29 PGE2 • Addition % PGE2 • None 100 • ACS18, 0.1 ug/ml 96 • ACS18, 1 ug/ml 59 • DuP-697, 0.1 ug/ml 56 • DuP-697, 1 ug/ml 27 • The mean value of 4 determinations each repeated in duplicate is shown

  12. PGE2 binds to EP2-Rs which are present in lung cancer cell lines

  13. 3H-PGE2 binds with high affinity to NSCLC membranes. Casibang and Moody, (2002) Lung Cancer 36:33.

  14. PGE1, PGE2, PGF2α and AH6809 bind with high affinity to NCI-H157 membranes. Compound IC50, ųM Arachidonic acid >10 AH6809 5 + 0.7 PGD2 >10 PGE1 0.2 + .03 PGE2 0.04 + .01 PGF2α 2 + 0.2 PGG2 >10 PGI2 >10

  15. The EP2 receptor is coupled to adenylylcyclase. ●PGE2 is an agonist which increases the cAMP in lung cancer ●AH6809 is an antagonist which reversibly blocks the receptor

  16. EP2 receptor antagonists block the increase in cAMP caused by PGE2.

  17. VEGF expression in lung cancer cells is increased by many agents. Casibang et al. (2001), Lung Cancer 31:203.

  18. VEGF mRNA is increased by PGE2 in a PKA-dependent manner Addition Relative VEGF mRNA None 100 + 5 PGE2, 1 uM 200 + 17* EGF, 0.1 ug/ml 185 + 16* H89, 50 uM 104 + 3 PGE2 + H89 110 + 6 The mean value + S.D. of 4 determinations is indicated; p < 0.05, *

  19. VEGF is secreted from NCI-H157 cells. Addition VEGF, pg/ml None 1023 + 57 PGE2, 1 uM 1240 + 76* Forskolin, 50 uM 1365 + 106* The mean value + S.D. of 4 determinations is indicated; p < 0.05, *

  20. Novel NSAIDs reduce cancer cellular growthHT29 H1299 MCF7Colon NSCLC BreastACS2 100 40 30ACS15 40 25 50ACS18 50 50 20Diclofenac 50 10 30 Sulindac 30 40 50Asp-NO 15 15 20The mean IC50 (ug/ml) is indicated using the MTT assay .

  21. Novel NSAIDs inhibit NSCLC colony formation Addition IC50, ug/ml Asp-NO 5 ACS2 20 ACS15 7 ACS18 8 The mean value of 3 determinations is indicated for NCI-H1299 colonies

  22. ACS2 inhibits lung cancer colony growth

  23. EGFR LUNG COX-2 CANCER CELL PGE2 SIGNAL EP2-R TRANSDUCTION Adenylyl cyclase Protein kinase A CREB phosphorylation Altered VEGF expression

  24. TGF α EGFR EGFR Release COX-2 TRANSACTIVATION Protease Activation PGE2 BY PGE2 Src Activation EP2-R Adenylyl cyclase Protein kinase A CREB phosphorylation Altered VEGF expression

  25. Some NSCLC patients, who have failed chemotherapy, respond to tyrosine kinase inhibitors • In the IDEAL-1 and IDEAL-2 clinical trials, 250 mg of gefitinib caused an objective response in approximately 50% of the patients. • Tumor responsiveness was not associated with EGFR expression but rather EGFR genetic mutations. • EGFR mutations occurred in exons 18 through 21 of the tyrosine kinase domain, such as G719S or L858R.

  26. Conclusions1. S-NSAIDs reduce PGE2 levels. In HT-29 cells DuP-697, which inhibits COX-2, strongly reduces PGE2 concentrations. These results suggest that S-NSAIDs are primarily inhibiting COX-2 in colon cancer cells.2. S-NSAIDs inhibit the proliferation of breast cancer, colon cancer and NSCLC cells.The CRBF is starting to investigate the effects of S-NSAIDS in animal models of cancer3. It remains to be determined if S-NSAIDs alter VEGF production in and secretion from cancer cells.

  27. AcknowledgmentsNCINIDDKM. Espey M. BernaL. Ridnour R.T. JensenC. SwitzerCTG pharmaD. Wink P. Del Soldato

More Related