RESUMO
Oridonin (Ori), a diterpenoid compound extracted from traditional medicinal herbs, elicits antitumor effects on many cancer types. However, whether Ori can be used in gefitinib-resistant non-small cell lung cancer (NSCLC) cells remains unclear. This study investigated the antitumor activity and underlying mechanisms of Ori. Results demonstrated that this compound dose-dependently inhibited the proliferation, invasion, and migration of the gefitinib-resistant NSCLC cells in vitro. Ori also significantly downregulated the phosphorylation of EGFR, ERK, Akt, expression levels of matrix metalloproteinase-12 (MMP-12), and the cancerous inhibitor of protein phosphatase 2A (CIP2A). In addition, Ori upregulated protein phosphatase 2A (PP2A) activity of gefitinib-resistant NSCLC cells. Ori combined with docetaxel synergistically inhibited these cells. Ori also inhibited tumor growth in murine models. Immunohistochemistry results further revealed that Ori downregulated phospho-EGFR, MMP-12, and CIP2A in vivo. These findings indicated that Ori can inhibit the proliferation, invasion, and migration of gefitinib-resistant NSCLC cells by suppressing EGFR/ERK/MMP-12 and CIP2A/PP2A/Akt signaling pathways. Thus, Ori may be a novel effective candidate to treat gefitinib-resistant NSCLC.
Assuntos
Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Diterpenos do Tipo Caurano/administração & dosagem , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Neoplasias Pulmonares/tratamento farmacológico , Quinazolinas/administração & dosagem , Células A549 , Animais , Autoantígenos/metabolismo , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Diterpenos do Tipo Caurano/farmacologia , Relação Dose-Resposta a Droga , Receptores ErbB/metabolismo , Gefitinibe , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Peptídeos e Proteínas de Sinalização Intracelular , Neoplasias Pulmonares/metabolismo , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Metaloproteinase 12 da Matriz/metabolismo , Proteínas de Membrana/metabolismo , Camundongos , Fosforilação/efeitos dos fármacos , Quinazolinas/farmacologia , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
It has been a long time since ultrasound hyperthermia began to be used in the clinical management of cancers and benign diseases. Numerous biological and clinical investigations have demonstrated that: hyperthermia in the range of 41-45 degrees C can significantly enhance clinical response to radiation therapy and chemotherapy, and high-temperature hyperthermia (greater than 65 degrees C) alone is now being used as an alternative to conventional invasive surgery for selective tissue destruction, causing tumor coagulation and necrosis. As a promising noninvasive and effective local therapy, HIFU has attracted great attention. China is advanced in the clinical applications of HIFU. This article gives an introduction of the development and applications of ultrasound hyperthermia technology, and also provides a general review of a selection of ultrasound hyperthermia systems both in clinical use and under development.