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Impact of combined treatment with nimesulide and cisplatin on oral carcinoma cells

Authors Barac A, Mitulovic G, Hallström S, Zehetmayer S, Grasl MC, Erovic BM

Received 26 December 2016

Accepted for publication 26 April 2017

Published 19 July 2017 Volume 2017:10 Pages 3607—3616

DOI https://doi.org/10.2147/OTT.S131106

Checked for plagiarism Yes

Review by Single-blind

Peer reviewers approved by Dr Akshita Wason

Peer reviewer comments 2

Editor who approved publication: Dr William Cho

Aleksandra Barac,1 Goran Mitulovic,2 Seth Hallström,3 Sonja Zehetmayer,4 Matthaeus Ch Grasl,5 Boban M Erovic5

1Clinic for Infectious and Tropical Diseases, Clinical Center of Serbia, Belgrade, Serbia; 2Medical and Chemical Laboratory Diagnostics, Medical University of Vienna, Vienna, Austria; 3Institute of Physiological Chemistry, Center for Physiological Medicine, Medical University of Graz, Graz, Austria; 4Medical Statistics, Medical University of Vienna, Vienna, 5Department of Otorhinolaryngology, Head and Neck Surgery, Medical University of Vienna, Vienna, Austria

Background: Despite significant advances in diagnosis and therapy, the rate of survival of patients with oral cancers still remains poor as an appropriate treatment has not been found yet, due to side effects of chemo/radiotherapy.
Aim: This study aimed to identify molecular mechanisms of cell death of oral cancer cells caused by treatment with a nonselective Cox-2 inhibitor in combination with a low-dose chemotherapeutic drug.
Methods: Squamous cell carcinoma (SCC) cells SCC9 and SCC25 were subjected to mono- and combination therapy with nimesulide and cisplatin. Fluorescence-activated cell sorting (FACS), immunohistochemistry, high-pressure liquid chromatography (HPLC), microarray gene chips, and isobaric tags for a relative and absolute quantitation (iTRAQ) system were used.
Results: Increased numbers of apoptotic and necrotic SCC9/SCC25 cells were detected after combined exposure. ATP levels and the energy charge of SCC9 cells were significantly decreased after both individual and combined treatment. We detected and quantified a responsible gene, keratin 6a, and 540 relevant proteins. In SCC25 cells, ATP levels significantly decreased only after combination therapy. After combined treatment of SCC9 cells, significant upregulation of Histon-H2A/H2B/H4 was found, with a local discovery false rate of 0.003 for Histon-H2A and 0.0027 for Histon-H2B, respectively.
Conclusion: Compared to the single-drug treatment, combined treatment of the oral cancer cells with nimesulide and cisplatin increases and induces necrosis and apoptosis through different pathways. A significant effect of the cytoplasmic increase was also observed in histones of cell lines SCC9 and SCC25 that were previously treated with combined nimesulide and cisplatin therapy.

Keywords: apoptosis, nimesulide, cisplatin, gene microarrays, combined therapy

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