Antiproliferative effect of two novel COX-2 inhibitors on human keratinocytes

作者：Sticozzi Claudia; Belmonte Giuseppe; Cervellati Franco; Di Capua Angela; Maioli Emanuela; Cappelli Andrea; Giordani Antonio; Biava Mariangela; Anzini Maurizio; Valacchi Giuseppe^*

来源：European Journal of Pharmaceutical Sciences, 2013, 49(2): 133-141.

DOI：10.1016/j.ejps.2013.02.009

• COX-2 inhibitor
• 1,5-Diarylpyrrole-3-alkopyrrole-3-alkoxyethyl ethers
• Cyclin D1
• p21

Selective COX-2 inhibitors (COXib) belonging to the class of diaryl heterocycles (e.g., celecoxib, rofecoxib, etc.), are devoid of the undesirable effects due to their capacity to inhibit selectively inducible (COX-2), responsible for inflammatory effects but not constitutive cyclooxygenase-1 (COX-1)(COX); responsible for cytoprotective effects on gastric mucosa. In addition, several reports have identified an increased risk of cardiovascular events associated with the use of COXib. We have developed a new series of anti-inflammatory agents (1,5-diarylpyrrole-3-alkoxyethyl esters and ethers). %26lt;br%26gt;To evaluate the effect of two 1,5-diarylpyrrole-3-alkoxyethyl ethers, VA441 and VA428 (up to 100 mu M), respectively, in comparison with two well known COXib, celecoxib and rofecoxib, on HaCaT cell (keratinocytes) proliferation and toxicity. %26lt;br%26gt;Crucial molecules in cell cycle progression, i.e. NF kappa B and ERK as targets/mediators and cyclin D1 and p21 Cip1/Kip as final effectors were evaluated by Western blot, immunohystochemistry and q-PCR analysis. %26lt;br%26gt;Both compounds, VA441 and VA428, showed a strong inhibition of cell proliferation, and did not exhibit cytotoxicity. The anti-proliferative effect was accompanied by a strong activation of ERK and induction of the cell cycle inhibitor p21. In addition, there was a clear inhibition of the transcription factor NF-kappa B and downregulation of cyclin D1, with enforced inhibition of the HaCaT cell cycle progression. %26lt;br%26gt;These data suggest that compounds VA441 and VA428, along with their role in inhibiting COX-2 and inflammation, could have a possible therapeutic (topical and systemic) use against skin proliferative disorders, such as psoriasis.

• 出版日期2013-5-13