Oncomedicine 2017; 2:28-36. doi:10.7150/oncm.17020 This volume

Research Paper

COX-2 Inhibitors, a Potential Synergistic Effect with Antineoplastic Drugs in Lung Cancer

Wolfgang Hohenforst-Schmidt1, Kalliopi Domvri2, Nikolaos Zogas3, Paul Zarogoulidis2✉, Savvas Petanidis4, Efrosini Kioseoglou4, George Zachariadis5, Stylianos Kakolyris6, Konstantinos Porpodis2, Mina Gaga7, Haidong Huang8, Theodor Kontakiotis2, Konstantinos Zarogoulidis2

1. II Medical Clinic, Hospital Coburg, University of Wurzburg, Coburg, Germany;
2. Pulmonary Department-Oncology Unit, “G. Papanikolaou” General Hospital, Aristotle University of Thessaloniki, Thessaloniki, Greece;
3. Gene and Cell Therapy Center, Hematology Department-Bone Marrow Transplantation Unit, “G. Papanikolaou” General Hospital, Thessaloniki, Greece;
4. Department of Chemical Engineering, Aristotle University of Thessaloniki, Thessaloniki 54124, Greece;
5. Laboratory of Biochemistry, School of Chemistry, Aristotle University of Thessaloniki, Thessaloniki, Greece;
6. Oncology Department, University General Hospital of Alexandroupolis, Democritus University of Thrace, Alexandroupolis, Greece;
7. 7th Respiratory Medicine Department and Asthma Center, Athens Chest Hospital 'Sotiria', Athens, Greece;
8. Pulmonary Department of the 2nd Military University Hospital of Shanghai, Shanghai, China.

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Hohenforst-Schmidt W, Domvri K, Zogas N, Zarogoulidis P, Petanidis S, Kioseoglou E, Zachariadis G, Kakolyris S, Porpodis K, Gaga M, Huang H, Kontakiotis T, Zarogoulidis K. COX-2 Inhibitors, a Potential Synergistic Effect with Antineoplastic Drugs in Lung Cancer. Oncomedicine 2017; 2:28-36. doi:10.7150/oncm.17020. Available from /v02p0028.htm

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Background: Lung cancer represents the leading cause of cancer-related deaths worldwide and novel therapeutic approaches targeting crucial pathways are urgently needed to improve its treatment. Inflammation plays a critical role in multistage tumor development and increased evidence has supported the involvement of cyclooxygenase-2 expression in carcinogenesis. We investigated the potential use of COX-2 inhibitors in cancer proliferation and apoptosis.

Methods: Celecoxib, rofecoxib, etoricoxib, meloxicam, ibufrofen and indomethacin are the COX-2 inhibitors included in this study. Docetaxel and Cisplatin are the chemotherapeutic agents that we combined with COX-2 inhibitors. Lung cancer cell lines (NCI-H1048-Small cell lung cancer, A549- Non-small cell lung cancer) were purchased from ATCC LGC Standards. At indicated time-point, following 24h and 48h incubation, cell viability and apoptosis were measured with Annexin V staining by flow cytometry. Statistical analysis was performed by GraphPad Prism.

Results: In Small cell lung cancer cells, following 24h incubation, combinations of docetaxel and meloxicam, docetaxel and ibuprofen, docetaxel and indomethacin, showed increased apoptosis when compared to docetaxel alone (p<0.0001). In Non-small cell lung cancer cells, the 24h incubation was not enough to induce satisfactory apoptosis, but following 48h incubation, docetaxel plus indomethacin showed more cytotoxicity when compared to docetaxel alone (p<0.0001). In addition, the combination of cisplatin plus indomethacin was the only combination to be found with higher cytotoxicity when compared to cisplatin alone after 48h treatment (p<0.0001).

Conclusion: Depending on the drug, the synergistic effect of COX-2 inhibitors plus chemotherapeutic agents has been demonstrated in lung cancer. Our suggestion is that COX-2 inhibitors could be used as additive and maintenance treatment in combination to antineoplastic agents in lung cancer patients.

Keywords: COX-2 inhibitors, lung cancer, in vitro.