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.

Lidocaine inhibits the invasion and migration of TRPV6-expressing cancer cells by TRPV6 downregulation

“…Chang et al (16) found that lidocaine and bupivacaine may be ideal infiltration anesthetics for breast cancer surgery as they could induce apoptosis of human breast cancer cells at clinically relevant concentrations, and since they demonstrated potential benefits of local anesthetics. Subsequently, after investigating lidocaine and bupivacaine treatment in human thyroid cancer cells, the study also found a significant decrease in cell viability and colony formation in a dose-dependent manner as the result of treatment with lidocaine and bupivacaine at higher concentrations, and suggested that lidocaine and bupivacaine may induce cell apoptosis through the mitogen-activated protein kinase pathway (21). The present study assessed the cytotoxicity of lidocaine at 1 to 10 mM and also found that lidocaine was able to significantly decreased cell viability of MDA-MB-231, PC-3 and ES-2 cells in a concentration-dependent manner.…”

Amide-linked local anesthetics induce apoptosis in human non-small cell lung cancer

“…Cleaved caspase-3, the active form of caspase-3, was the capital cleavage enzyme in apoptosis (13). Apoptosis was characterized by the nuclear DNA degradation in response to a variety of apoptotic stimuli (35,36).…”

“…It seems to be unrelated to the sodium-channel blockade (8)(9)(10), while in other reports local anesthetics work in the manner of inhibiting the activity of sodium channels (11,12). Previous study has suggested that local anesthetics could induce apoptosis in human thyroid cancer cells, which is associated with mitogen-activated protein kinase (MAPK) pathways (13). Another report has suggested that inhibition of MAPK pathways protects against local anesthetics-induced neurotoxicity (14).…”

CD74 expression and its therapeutic potential in thyroid carcinoma

“…Colony formation assay was performed as previously described (Chang et al 2014). In brief, BCPAP (1000 cells/ well) and K1 cells (500 cells/well) were seeded into six-well plates, allowed to adhere for 24 h, and treated with isotype control, recombinant human MIF (200 ng/ml) or anti-CD74 antibody (5 mg/ml) from day 2.…”