RESUMEN
Purpose: Hyperthermia (HT), a clinical treatment involving delivery of heat to tumors, has been used in combination with traditional chemotherapy and radiotherapy to enhance their effects. However, the molecular mechanism underlying the high efficacy of combination therapy is not clear. This study was conducted to identify the molecular mechanism underlying the sensitization of lung cancer to radiotherapy by HT.Materials and methods: Nuclear receptor subfamily 4, group A, member 3 (NR4A3) and Krüppel-like factor 11 (KLF11) expression in non-small-cell lung cancer cells was confirmed by performing real-time quantitative reverse transcription-polymerase chain reaction. Tumor cell proliferation and apoptosis were assessed via a colony-forming assay and Annexin V/propidium iodide staining.Results and conclusions: Expression profile analysis revealed elevated levels of NR4A3 and KLF11 in A549 lung cancer cells after treatment with HT combined with radiation. We also confirmed that NR4A3 and KLF11 induced apoptosis and inhibited cell proliferation by elevating intracellular reactive oxygen species levels. Knockdown of NR4A3 or KLF11 using siRNA led to decreased effects of radiohyperthermia. Finally, the effect of these two factors on lung cancer progression was evaluated by in vivo xenograft studies. Taken together, the results suggest that NR4A3 and KLF11 are critical for increasing the efficacy of radiotherapy in combination with HT.
Asunto(s)
Proteínas Reguladoras de la Apoptosis/genética , Proteínas de Unión al ADN/genética , Progresión de la Enfermedad , Regulación Neoplásica de la Expresión Génica/efectos de la radiación , Hipertermia Inducida , Neoplasias Pulmonares/patología , Neoplasias Pulmonares/radioterapia , Receptores de Esteroides/genética , Receptores de Hormona Tiroidea/genética , Proteínas Represoras/genética , Células A549 , Animales , Apoptosis/efectos de la radiación , Proliferación Celular/efectos de la radiación , Transformación Celular Neoplásica , Terapia Combinada , Humanos , Neoplasias Pulmonares/genética , Masculino , RatonesRESUMEN
Hyperthermia is a cancer treatment where tumor tissue is heated to around 40 °C. Hyperthermia shows both cancer cell cytotoxicity and immune response stimulation via immune cell activation. Immunogenic responses encompass the innate and adaptive immune systems, involving the activation of macrophages, natural killer cells, dendritic cells, and T cells. Moreover, hyperthermia is commonly used in combination with different treatment modalities, such as radiotherapy and chemotherapy, for better clinical outcomes. In this review, we will focus on hyperthermia-induced immunogenic effects and molecular events to improve radiotherapy efficacy. The beneficial potential of integrating radiotherapy with hyperthermia is also discussed.
Asunto(s)
Hipertermia Inducida/métodos , Neoplasias/terapia , Radioterapia/métodos , Animales , Terapia Combinada/métodos , Humanos , Inmunidad Celular , Inmunidad Innata , Inmunoterapia/métodos , Neoplasias/inmunología , Neoplasias/patología , Neoplasias/radioterapiaRESUMEN
Increased survival of cancer cells mediated by high levels of ionizing radiation (IR) reduces the effectiveness of radiation therapy for non-small cell lung cancer (NSCLC). In the present study, danshensu which is a selected component of traditional oriental medicine (TOM) compound was found to reduce the radioresistance of NSCLC by inhibiting the nuclear factor-κB (NF-κB) pathway. Of the various TOM compounds reported to inhibit the IR activation of NF-κB, danshensu was chosen as a final candidate based on the results of structural comparisons with human metabolites and monoamine oxidase B (MAOB) was identified as the putative target enzyme. Danshensu decreased the activation of NF-κB by inhibiting MAOB activity in A549 and NCI-H1299 NSCLC cells. Moreover, it suppressed IR-induced epithelial-to-mesenchymal transition, expressions of NF-κB-regulated prosurvival and proinflammatory genes, and in vivo radioresistance of mouse xenograft models. Taken together, this study shows that danshensu significantly reduces MAOB activity and attenuates NF-κB signaling to elicit the radiosensitization of NSCLC.