Enhancement of photodynamic therapy by 2,5-dimethyl celecoxib, a non-cyclooxygenase-2 inhibitor analog of celecoxib.

Abstract

Photodynamic therapy (PDT) effectiveness can be improved by employing combined modality approaches involving pharmaceuticals targeting the tumor microenvironment and/or tumor cell death pathways. In one approach, combining PDT with celecoxib improves long-term tumoricidal activity without increasing normal tissue photosensitization. However, side effects arising from the use of coxib based cyclooxygenase-2 (COX-2) inhibitors, including cardiovascular injury, decreases the clinical applications of this class of compounds. A growing number of studies demonstrate that the tumoricidal actions of coxibs such as celecoxib involve non-COX-2 mediated mechanisms. The celecoxib analog, 2,5-dimethyl celecoxib (DMC), lacks COX-2 inhibitory activity but exhibits cytotoxic properties comparable to the COX-2 inhibitor celecoxib. We compared the effectiveness of DMC and celecoxib in modulating PDT response at both the in vitro and in vivo level using a C3H/BA murine mammary carcinoma model. Both DMC and celecoxib blocked PDT induced expression of the pro-survival protein survivin, enhanced the endoplasmic reticulum stress (ERS) response of PDT, and increased both apoptosis and cytotoxicity in BA cells exposed to combination protocols. DMC enhanced the in vivo tumoricidal responsiveness of PDT without altering PGE2 levels. Our data demonstrates that DMC improved PDT by increasing apoptosis and tumoricidal activity without modulating COX-2 catalytic activity. Our results also suggest that celecoxib mediated enhancement of PDT may involve both COX-2 dependent and independent mechanisms.

• Authors: Angela Ferrario, Sophia Lim, Frank Xu, Marian Luna, Kevin J Gaffney, Nicos A Petasis, Axel H Schönthal, Charles J Gomer
• Journal: Cancer letters (Cancer Lett) Vol. 304 Issue 1 Pg. 33-40 (May 01 2011) ISSN: 1872-7980 [Electronic] Ireland
• PMID: 21339042 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.

Chemical References

• 2,5-dimethylcelecoxib
• Cyclooxygenase 2 Inhibitors
• Photosensitizing Agents
• Pyrazoles
• Sulfonamides
• Dihematoporphyrin Ether
• Cyclooxygenase 2

Topics

• Animals
• Apoptosis (drug effects, radiation effects)
• Cell Line, Tumor
• Cyclooxygenase 2 (metabolism)
• Cyclooxygenase 2 Inhibitors (therapeutic use)
• Dihematoporphyrin Ether (therapeutic use)
• Drug Synergism
• Endoplasmic Reticulum (drug effects)
• Female
• Light
• Mammary Neoplasms, Animal (drug therapy, enzymology, pathology)
• Mice
• Mice, Inbred C3H
• Photochemotherapy
• Photosensitizing Agents (therapeutic use)
• Pyrazoles (therapeutic use)
• Sulfonamides (therapeutic use)