Microwave hyperthermia promotes caspase‑3-dependent apoptosis and induces G2/M checkpoint arrest via the ATM pathway in non‑small cell lung cancer cells

Abstract

Post-operative microwave (MW) hyperthermia has been applied as an important adjuvant therapy to enhance the efficacy of traditional cancer treatment. A better understanding of the molecular mechanisms of MW hyperthermia may provide guided and further information on clinical hyperthermia treatment. In this study, we examined the effects of MW hyperthermia on non-small cell lung carcinoma (NSCLC) cells in vitro, as well as the underlying mechanisms. In order to mimic clinical treatment, we developed special MW heating equipment for this study. Various NSCLC cells (H460, PC-9 and H1975) were exposed to hyperthermia treatment using a water bath or MW heating system. The results revealed that MW hyperthermia significantly inhibited cell growth compared with the water bath heating system. Furthermore, MW hyperthermia increased the production of reactive oxygen species (ROS), decreased the levels of mitochondrial membrane potential (MMP) and induced caspase-3 dependent apoptosis. It also induced G2/M phase arrest through the upregulation of the expression of phosphorylated (p-) ataxia telangiectasia mutated (ATM), p-checkpoint kinase 2 (Chk2) and p21, and the downregulation of the expression of cdc25c, cyclin B1 and cdc2. On the whole, the findings of this study indicate that the exposure of NSCLC cells to MW hyper-thermia promotes caspase-3 dependent apoptosis and induces G2/M cell cycle arrest via the ATM pathway. This preclinical study may help to provide laboratory-based evidence for MW hyperthermia treatment in clinical practice.

Thermally driven fission of protocells

“…Although the very notion of temperature at this scale and far from a thermodynamical equilibrium is not clear, the measurement of the temperature variations inside the cell during its life cycle could be correlated with the onset of mitosis and with the activity of the mitochondrial network (31,32). Our proposition is also coherent with the fact that hyperthermia can block the cell cycle at the G2/M checkpoint (33).…”

“…Let us add that the thermal gradient still plays an important role in the division of modern cells because hyperthermia can block the cell cycle just before mitosis, as observed experi-mentally on lung cancer cells (33). This is why we consider our proposition as a first step toward a more detailed model that would take into account other thermodynamical forces, such as the membrane electric potential or ionic concentration differences (34), to explain the fission of protocells.…”

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

“…High-temperature stimulation leads to several physiological responses, including changes in the membrane permeability or cytoskeleton system, alteration in macromolecule synthesis or intracellular signaling, and inhibition of DNA repair [ 10 ]. In lung cancer, hyperthermia treatment induces cell death via cytoskeletal alteration [ 11 ], an increase in caspase-3-dependent apoptosis [ 12 ], or the induction of reactive oxygen species-related autophagy [ 13 ]. In addition, the effects of gemicitabine [ 14 ], paclitaxel/carboplatin [ 15 ], doxorubicin [ 16 ], cisplatin [ 17 ], or even radiotherapy [ 18 ] can be increased when combined with hyperthermia.…”

Interfering with Tumor Hypoxia for Radiotherapy Optimization

“…As part of a combined treatment with chemo- or radiotherapy, hyperthermia is already approved for routine clinical use in several countries. The radiosensitizing effect is thought to occur due to the improvement of oxygen delivery to the tissue [ 290 , 291 ] and due to interference with the DNA damage response [ 292 – 298 ]. Cytotoxic effects can be direct and indirect: heat can directly induce necrosis, apoptosis and mitotic catastrophe [ 299 – 301 ] and with an applied temperature above 42 °C, heat will indirectly kill by inducing vascular damage [ 302 ].…”