Abstract
Squamous cell carcinoma (SCC) remains a main cause of mortality in patients with neck and head cancers, with poor prognosis and increased prevalence despite of available therapies. Recent studies have identified a role of cyclooxygenases, particularly inducible isoform cyclooxygenase-2 (COX-2) and its metabolite prostaglandin E2 (PGE2) in cancer cell proliferation, and its inhibition become a target for control of cancer development, particularly in the view of recognized additive or synergic action of COX-2 inhibitors with other forms of therapy. Nimesulide (N), the selective COX-2 inhibitor, inhibits growth and proliferation of various types of cancer cells by COX-2 dependent and independent mechanisms. In the presented study, the conjugates of biotinylated third generation poly(amidoamine) dendrimer (PAMAM) with covalently linked 18 (G3B18N) and 31 (G3B31N) nimesulide residues were synthesized and characterized by NMR spectroscopy. Biological properties of conjugates were evaluated, including cytotoxicity, proliferation, and caspase 3/7 activities in relation to COX-2/PGE2 axis signaling in human normal fibroblast (BJ) and squamous cell carcinoma (SCC-15). Both conjugates exerted a selective cytotoxicity against SCC-15 as compared with BJ cells at low 1.25–10 µM concentration range and their action in cancer cells was over 250-fold stronger than nimesulide alone. Conjugates overcome apoptosis resistance and sensitized SCC-15 cells to the apoptotic death independently of COX-2/PGE2 axis. In normal human fibroblasts the same concentrations of G3B31N conjugate were less effective in inhibition of proliferation and induction of apoptosis, as measured by caspase 3/7 activity in a manner depending on increase of PGE2 production by either COX-1/COX-2.
Highlights
Squamous cell carcinoma (SCC-15) is a malignant tumor of squamous epithelium that may occur in many different organs, including skin
Current treatment strategies for Oral squamous cell carcinoma (OSCC) include surgery, chemo, radio, and photodynamic therapies often combined with epidermal growth factor receptor (EGFR) antagonists or cyclooxygenase-2 (COX-2) inhibitors, the last ones remaining under intensive elucidations [3]
Substitution of biotinylated poly(amidoamine) dendrimer (PAMAM) G3 dendrimers with 18 (G3B18N ) or 31 (G3B31N ) nimesulide residues remarkably increased activity of this drug compared to its native form
Summary
Squamous cell carcinoma (SCC-15) is a malignant tumor of squamous epithelium that may occur in many different organs, including skin. Oral squamous cell carcinoma (OSCC) is the most common malignant tumor of the oral cavity, accounting for over 90% of the malignant neoplasms in this. Biomolecules 2019, 9, 437 location and is the sixth most common cancer in the world, with increasing incidences and five-year survival rate despite the available therapy [1,2]. Current treatment strategies for OSCC include surgery, chemo-, radio-, and photodynamic therapies often combined with epidermal growth factor receptor (EGFR) antagonists or cyclooxygenase-2 (COX-2) inhibitors, the last ones remaining under intensive elucidations [3]. Many studies have identified the role of COXs in cancer development and progression [7] Three isoforms of COX are presently recognized: ubiquitously expressed constitutive COX-1, which is involved in homeostasis of vital physiological functions in most tissues, inducible COX-2 isoform, expressed during both inflammation and cancer, and COX-3, identified in human cerebral cortex and heart [5,6].
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