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

Abstract

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.

The comparison analysis of polyphyllin I and its analogues induced apoptosis of colon and lung cancer cells via mitochondrial dysfunction

“…There are two main pathways involved in the process of apoptosis, the internal (or mitochondrial) pathway and the external (or death receptor) pathway 30 . Various small‐molecule compounds have the potential of curing cancers by inducing cancer cell apoptosis 31 . The mechanism of mitochondrial‐mediated apoptosis mainly depends on mitochondrial dysfunction, including the loss of MMP, Ca 2+ overload and the elevated ROS levels 32 .…”

Design, Synthesis, Biological Evaluation and In Silico Study of Benzyloxybenzaldehyde Derivatives as Selective ALDH1A3 Inhibitors

“…Cinnamaldehyde has been found to be cytotoxic on several cancer cell lines, such as leukemia K562 [ 41 ] and breast cancer MCF-7 cells [ 42 ]. Furthermore, cinnamaldehyde has been found to be a promising adjuvant candidate in combination with 5-fluorouracil and oxaliplatin against colorectal carcinoma [ 43 ], and to enhance the apoptosis induced by hyperthermia against the A549 cells [ 44 ] and by doxorubicin on glioblastoma cells (U87MG) [ 45 ]. This cytotoxicity of cinnamaldehyde may be due to the presence of an electrophilic Michael acceptor (α,β-unsaturated aldehyde) pharmacophore, which has been anticipated to provide this scaffold with a potential anticancer activity [ 46 ].…”

Ethanol Enhances Hyperthermia-Induced Cell Death in Human Leukemia Cells

“…Nanoparticles with appropriate external energy sources are being used for local treatment [ 45 , 46 , 47 ]. Strategies to enhance the therapeutic efficacy of hyperthermia are also under investigation; in this context cytotoxic properties of hyperthermia on leukemia, melanoma, lung carcinoma, and colon cancer cells, among others, have been improved by the use of compounds that sensitize to the cells [ 19 , 20 , 21 , 22 , 23 , 24 , 25 , 26 , 27 ]. In the present study the effect of ethanol on cytotoxicity exhibited by hyperthermia on leukemia cells was investigated since this alcohol has been reported to enhance the antitumor properties of radiation and the effectiveness of chemotherapeutic agents like TRAIL [ 29 , 30 , 31 , 32 , 34 ].…”

“…Consequently, the possibility to reduce thermotolerance by using low toxicity compounds is of great clinical importance. In this regard, several studies in vivo and in vitro have explored non-toxic enhancers for hyperthermia-induced cell death in a variety of human cancer cells including lung cancer [ 19 , 20 ], colon cancer [ 21 , 22 ], melanoma [ 23 ], and leukemia cells [ 24 , 25 , 26 , 27 ].…”