Combination Therapy with Cinnamaldehyde and Hyperthermia Induces Apoptosis of A549 Non-Small Cell Lung Carcinoma Cells via Regulation of Reactive Oxygen Species and Mitogen-Activated Protein Kinase Family

Lung cancer is the largest cause of cancer-induced deaths. Non-small cell lung cancer (NSCLC) is the most frequently observed subtype of lung cancer. Although recent studies have provided many therapeutic options, there is still a need for effective and safe treatments. This paper reports the combined effects of cinnamaldehyde (CNM), a flavonoid from cinnamon, together with hyperthermia, a therapeutic option for cancer treatment, on the A549 NSCLC cell line. A hyperthermia treatment of 43 °C potentiated the cytotoxicity of CNM in A549 cells. This was attributed to an increase in the apoptosis markers and suppression of the survival/protective factors, as confirmed by Western blot assays. Flow cytometry supported this result because the apoptotic profile, cell health profile, and cell cycle profile were regulated by CNM and hyperthermia combination therapy. The changes in reactive oxygen species (ROS) and its downstream target pathway, mitogen-activated protein kinases (MAPK), were evaluated. The CNM and hyperthermia combination increased the generation of ROS and MAPK phosphorylation. N-acetylcysteine (NAC), a ROS inhibitor, abolished the apoptotic events caused by CNM and hyperthermia co-treatment, suggesting that the cytotoxic effect was dependent of ROS signaling. Therefore, we suggest CNM and hyperthermia combination as an effective therapeutic option for the NSCLC treatment.

Keywords: apoptosis; cinnamaldehyde; hyperthermia therapy; mitogen-activated protein kinase; non-small cell lung cancer; reactive oxygen species; synergy.