Cyclooxygenase-2 is a possible target of treatment approach in conjunction with photodynamic therapy for various disorders in skin and oral cavity

Y. Akita, K. Kozaki, T. Nakagawa, S. Saito, Ito, S. Tamada, N. Fujiwara, K. Nishikawa, K. Uchida, T. Yoshikawa, O. Noguchi, K. Miyaishi, S. Shimozato, Y. Saga, Matsumoto

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Abstract

Background: Anti-cancer effects of cyclooxygenase (COX)-2 inhibitors have been reported, but not fully investigated in skin and oral diseases. 5-aminolaevulinic acid (ALA)-based photodynamic therapy (PDT) for treating those patients with skin and oral lesions is a highly sophisticated procedure, but the incidence of disease recurrence after treatment is rather significant. Objective: To confirm that COX-2 could be a molecular target in adjunctive therapy to ALA-based PDT, we investigated (i) COX-2 expression in various skin and oral diseases, and (ii) the inhibitory effects on cellular growth of COX-2 selective inhibitor (nimesulide), ALA-based PDT and their combination on human oral squamous cell carcinoma (SCC) cell lines. Methods: A total of 129 biopsy samples from the skin and oral mucosal lesions were tested immunohistochemically for COX-2 expression. Then the in vitro effects of nimesulide, ALA-based PDT, and their combination were determined on two SCC cell lines, HSC-2 and HSC-4. Three different methods (MTT assay, double-staining for annexin V and propidium iodide, caspase-3/CPP32 fluorometric protease assay) were applied for evaluation of their inhibitory effects on these two cell lines. Results: Among the skin diseases, a considerable number of COX-2 high expressers were found in actinic keratosis (15 of 25, 60%), Bowen's disease (13 of 17, 76%) and extramammary Paget's disease (15 of 15, 100%). In contrast, only one of 33 (3%) basal cell carcinoma tumours was a COX-2 high expresser. Among the oral mucosal biopsies, the proportion of COX-2 high expressers increased gradually from hyperplasia (one of six, 17%) through mild dysplasia (five of eight, 63%) and moderate dysplasia (20 of 23, 87%) to severe dysplasia (two of two, 100%). Nimesulide had an inhibitory effect in vitro on HSC-2 (proven to be a COX-2 high expresser), but not on HSC-4 (a COX-2 non-expresser). While ALA-based PDT showed an inhibitory effect on both HSC-2 and HSC-4, most importantly the combination of nimesulide and ALA-based PDT demonstrated a significant synergistic effect on the cellular growth inhibition of only HSC-2, but not of HSC-4. Conclusions: Our study strongly suggests that COX-2 can be one of the molecular targets in treating various skin and oral diseases. The results from our in vitro experiments also prompt us to develop a new protocol with a combination of COX-2 selective inhibitor and ALA-based PDT for more effective treatment of those diseases.

Original languageEnglish
Pages (from-to)472-480
Number of pages9
JournalBritish Journal of Dermatology
Volume151
Issue number2
DOIs
Publication statusPublished - Aug 2004

Keywords

  • COX-2 inhibitor
  • Cyclooxygenase-2
  • Oral mucosa
  • Photodynamic therapy
  • Skin

ASJC Scopus subject areas

  • Dermatology

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    Akita, Y., Kozaki, K., Nakagawa, T., Saito, S., Ito, Tamada, S., Fujiwara, N., Nishikawa, K., Uchida, K., Yoshikawa, T., Noguchi, O., Miyaishi, K., Shimozato, S., Saga, Y., & Matsumoto (2004). Cyclooxygenase-2 is a possible target of treatment approach in conjunction with photodynamic therapy for various disorders in skin and oral cavity. British Journal of Dermatology, 151(2), 472-480. https://doi.org/10.1111/j.1365-2133.2004.06053.x