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

Abstract

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.

The Role of Zyxin in Carcinogenesis

“…It was shown that increased expression of COX-2 in non-small cell lung cancer (NSCLC) plays a significant role in lung cancer development through its effect on angiogenesis and immune response suppression in tumour cells (40,41). The literature data show that carcinogenesis can be decelerated by the use of COX-2 inhibitors not only as single agents, but also in combined therapy (40)(41)(42). Therefore, an increased level of ZYX in response to the application of COX-2 inhibitor suggests the ability of ZYX to inhibit oncogenesis.…”

Selective COX-2 Inhibitors: Road from Success to Controversy and the Quest for Repurposing

“…Another study suggested a limited dose-dependent effect on cell proliferation in human colorectal carcinoma cell lines [91]. In a study, rofecoxib (40 µM), in combination with docetaxel, was found to be more cytotoxic to lung cancer cell lines than docetaxel alone [92]. Rofecoxib was also reported to prevent DNA damage induced by ultraviolet B radiation and copper ions.…”