Cyclooxygenase inhibitors combined with deuterium-enriched water augment cytotoxicity in A۵۴۹ lung cancer cell line via activation of apoptosis and MAPK pathways

Objective(s): Combination chemotherapy is a rational strategy to increase patient response and tolerability and to decrease adverse effects and drug resistance. Recently, the use of non-steroidal anti-inflammatory drugs (NSAIDs) has been reported to be associated with reduction in occurrence of a variety of cancers including lung cancer. On the other hand, growing evidences suggest that deuterium-enriched water (DEW, D۲O) and deuterium-depleted water (DDW) play a role both in treatment and prevention of cancers. In the present study, we examined the effects of DEW and DDW in combination with two NSAIDs, celecoxib and indomethacin, on A۵۴۹ human non-small lung cancer cell to identify novel treatment options. Materials and Methods: The cytotoxicity of celecoxib or indomethacin, alone and in combination with DDW and DEW was determined. The COX-۲, MAPK pathway proteins, the anti-apoptotic Bcl۲ and pro-apoptotic Bax proteins and caspase-۳ activity were studied for cytotoxic combinations.Results: Co-administration of selective and non-selective COX-۲ inhibitors with DEW led to a remarkable increase in cytotoxicity and apoptosis of A۵۴۹ cells. These events were associated with activation of p۳۸ and JNK MAPKs and decreasing pro-survival proteins Bcl-۲, COX-۲ and ERK۱/۲. Furthermore, the combination therapy activated caspase-۳, and the apoptosis mediator, and disabled poly ADP-ribose polymerase (PARP), the key DNA repair enzyme, by cleaving it.  Conclusion: The combination of DEW with NSAIDs might be effective against lung cancer cells by influence on principal cell signalling pathways, and this has a potential to become a candidate for chemotherapy.

کلیدواژه ها:

A۵۴۹ lung cancer cell ، Apoptosis ، Combination therapy ، Cyclooxygenase inhibitors ، Deuterium enriched water ، MAPK pathway