title: Local anesthetics induce apoptosis in human thyroid cancer cells through the mitogen-activated protein kinase pathway.
abstract: 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.
authors.affiliation: Graduate Institute of Physiology, National Taiwan University College of Medicine, Taipei, Taiwan ; Department of Surgery, Mackay Memorial Hospital and Mackay Medical College, Taipei, Taiwan ; Mackay Junior College of Medicine, Nursing, and Management, Taipei, Taiwan.
authors.forename: Yuan-Ching
authors.initials: YC
authors.lastname: Chang
authors.affiliation: Institute of Statistical Science, Academia Sinica, Taipei, Taiwan.
authors.forename: Yi-Chiung
authors.initials: YC
authors.lastname: Hsu
authors.affiliation: Department of Surgery, Mackay Memorial Hospital and Mackay Medical College, Taipei, Taiwan ; Mackay Junior College of Medicine, Nursing, and Management, Taipei, Taiwan.
authors.forename: Chien-Liang
authors.initials: CL
authors.lastname: Liu
authors.affiliation: Department of Surgery, Mackay Memorial Hospital and Mackay Medical College, Taipei, Taiwan.
authors.forename: Shih-Yuan
authors.initials: SY
authors.lastname: Huang
authors.affiliation: Graduate Institute of Physiology, National Taiwan University College of Medicine, Taipei, Taiwan.
authors.forename: Meng-Chun
authors.initials: MC
authors.lastname: Hu
authors.affiliation: Department of Surgery, Mackay Memorial Hospital and Mackay Medical College, Taipei, Taiwan ; Mackay Junior College of Medicine, Nursing, and Management, Taipei, Taiwan ; Graduate Institute of Medical Sciences, Department of Pharmacology, Taipei Medical University, Taipei, Taiwan.
authors.forename: Shih-Ping
authors.initials: SP
authors.lastname: Cheng
mesh_terms: D000779:Anesthetics, Local / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D002045:Bupivacaine / Q000494:pharmacology*; D053148:Caspase 3 / Q000378:metabolism; D053179:Caspase 7 / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects; D045304:Cytochromes c / Q000378:metabolism; D004354:Drug Screening Assays, Antitumor; D004789:Enzyme Activation; D015870:Gene Expression / Q000187:drug effects; D006801:Humans; D008012:Lidocaine / Q000494:pharmacology*; D020935:MAP Kinase Signaling System / Q000187:drug effects*; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D008928:Mitochondria / Q000187:drug effects / Q000502:physiology; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D013964:Thyroid Neoplasms
chemical_list: D000779:Anesthetics, Local; D000970:Antineoplastic Agents; D045304:Cytochromes c; D008012:Lidocaine; C499320:PARP1 protein, human; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases; C505407:CASP3 protein, human; C505520:CASP7 protein, human; D053148:Caspase 3; D053179:Caspase 7; D002045:Bupivacaine