Local Anesthetics Induce Apoptosis in Human Thyroid Cancer Cells through the Mitogen-Activated Protein Kinase Pathway

被引:114
作者
Chang, Yuan-Ching [1 ,2 ,3 ,5 ]
Hsu, Yi-Chiung [4 ]
Liu, Chien-Liang [2 ,3 ,5 ]
Huang, Shih-Yuan [2 ,3 ]
Hu, Meng-Chun [1 ]
Cheng, Shih-Ping [2 ,3 ,5 ,6 ]
机构
[1] Natl Taiwan Univ, Coll Med, Grad Inst Physiol, Taipei 10764, Taiwan
[2] Mackay Mem Hosp, Dept Surg, Taipei, Taiwan
[3] Mackay Med Coll, Taipei, Taiwan
[4] Acad Sinica, Inst Stat Sci, Taipei 11529, Taiwan
[5] Mackay Jr Coll Med Nursing & Management, Taipei, Taiwan
[6] Taipei Med Univ, Dept Pharmacol, Grad Inst Med Sci, Taipei, Taiwan
关键词
PERCUTANEOUS ETHANOL INJECTION; GROWTH-FACTOR RECEPTOR; IN-VITRO; RADIOFREQUENCY ABLATION; INDUCED NEUROTOXICITY; SIGNALING PATHWAYS; LIDOCAINE; INHIBITION; PAPILLARY; EXPRESSION;
D O I
10.1371/journal.pone.0089563
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
070301 [无机化学]; 070403 [天体物理学]; 070507 [自然资源与国土空间规划学]; 090105 [作物生产系统与生态工程];
摘要
Local anesthetics are frequently used in fine-needle aspiration of thyroid lesions and locoregional control of persistent or recurrent thyroid cancer. Recent evidence suggests that local anesthetics have a broad spectrum of effects including inhibition of cell proliferation and induction of apoptosis in neuronal and other types of cells. In this study, we demonstrated that treatment with lidocaine and bupivacaine resulted in decreased cell viability and colony formation of both 8505C and K1 cells in a dose-dependent manner. Lidocaine and bupivacaine induced apoptosis, and necrosis in high concentrations, as determined by flow cytometry. Lidocaine and bupivacaine caused disruption of mitochondrial membrane potential and release of cytochrome c, accompanied by activation of caspase 3 and 7, PARP cleavage, and induction of a higher ratio of Bax/Bcl-2. Based on microarray and pathway analysis, apoptosis is the prominent transcriptional change common to lidocaine and bupivacaine treatment. Furthermore, lidocaine and bupivacaine attenuated extracellular signal-regulated kinase 1/2 (ERK1/2) activity and induced activation of p38 mitogen-activated protein kinase (MAPK) and c-jun N-terminal kinase. Pharmacological inhibitors of MAPK/ERK kinase and p38 MAPK suppressed caspase 3 activation and PARP cleavage. Taken together, our results for the first time demonstrate the cytotoxic effects of local anesthetics on thyroid cancer cells and implicate the MAPK pathways as an important mechanism. Our findings have potential clinical relevance in that the use of local anesthetics may confer previously unrecognized benefits in the management of patients with thyroid cancer.
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页数:11
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