Celecoxib and NS-398 Enhance Photodynamic Therapy by Increasing In vitro Apoptosis and Decreasing In vivo Inflammatory and Angiogenic Factors

Abstract

Photodynamic therapy (PDT) elicits both apoptotic and necrotic responses within treated tumors and produces microvascular injury leading to inflammation and hypoxia. PDT also induces expression of angiogenic and survival molecules including vascular endothelial growth factor, cyclooxygenase-2 (COX-2), and matrix metalloproteinases. Adjunctive administration of inhibitors to these molecules improves PDT responsiveness. In the current study, we examined how the combination of PDT and COX-2 inhibitors improve treatment responsiveness. Photofrin-mediated PDT combined with either celecoxib or NS-398 increased cytotoxicity and apoptosis in mouse BA mammary carcinoma cells. Immunoblot analysis of protein extracts from PDT-treated cells also showed poly(ADP-ribose) polymerase cleavage and Bcl-2 degradation, which were further enhanced following combined therapy. Tumor-bearing mice treated with PDT and either celecoxib or NS-398 exhibited significant improvement in long-term tumor-free survival when compared with PDT or COX-2 inhibitor treatments alone. The combined procedures did not increase in vivo tumor-associated apoptosis. Administration of celecoxib or NS-398 attenuated tissue levels of prostaglandin E 2 and vascular endothelial growth factor induced by PDT in treated tumors and also decreased the expression of proinflammatory mediators interleukin-1B and tumor necrosis factor-A. Increased tumor levels of the antiinflammatory cytokine, interleukin 10, were also observed following combined treatment. This study documents for the first time that adjunctive use of celecoxib enhances PDTmediated tumoricidal action in an in vivo tumor model. Our results also show that administration of COX-2 inhibitors enhance in vitro photosensitization by increasing apoptosis and improve in vivo PDT responsiveness by decreasing expression of angiogenic and inflammatory molecules. (Cancer Res 2005; 65(20): 9473-8)

Chemophototherapy: An Emerging Treatment Option for Solid Tumors

“…Photofrin–PDT induced the expression of 5 of 140 stress related genes and 1 of the 5 encodes for COX‐2 164. In contrast to the finding from Ferrario et al which demonstrated that combination of COX‐2 inhibitors potentiated PDT responses in vitro,150 addition of COX‐2 inhibitors, NS‐398, rofecoxib or nimesulide before or after PDT did not potentiate PDT responses in C‐26 cells. The COX‐2 inhibitor nimesulid given after, but not before PDT irradiation, significantly enhanced the anti‐tumor efficacy on C‐26 tumor bearing mice, resulting in complete response in the majority of (60% cure) treated mice.…”

Secreted Protein Acidic and Rich in Cysteine (SPARC) Mediates Metastatic Dormancy of Prostate Cancer in Bone

“…Furthermore, NS398 induced SPARC via down-regulation of DNMT1 and DNMT3b, which is in agreement with a previous study showing a DNMT-dependent increase of SPARC in A549 lung carcinoma cells by NS398 (29). In addition, NS398 has been studied previously for its effect on limiting cell proliferation, angiogenesis, invasion, and metastasis of multiple cancer types (65)(66)(67). It should be noted that NS398 was also shown previously to significantly inhibit bone metastasis of breast cancer cells by suppressing TGF-␤ dependent activation of COX-2.…”

Photochemically stimulated drug delivery increases the cytotoxicity and specificity of EGF–saporin

“…Increased cytotoxicity is reported after dual therapy with PDT and different chemotherapeutic drugs such as cisplatin (Nonaka et al 2002) cyclophosphamide (Casas et al 1998), 5-fluoro-2-deoxyuridine (5FdUr) (Zimmermann et al 2003), metotrexate and doxorubicin (Kirveliene et al 2006). Recently, novel anticancer drugs as TKIs (Dimitroff et al 1999, Liu et al 2007, mAbs (del Carmen et al 2005, Ferrario & Gomer 2006 and COX-2 inhibitors (Ferrario et al 2005) have been reported to enhance PDT-mediated toxicity. However, antagonistic responses have also been reported with PDT in combination with doxorubicin and 5FdUr (Zimmermann et al 2003, Kirveliene et al 2006.…”