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.
Highlights
Thyroid cancer is the most common of all endocrine cancers, and the incidence of thyroid cancer is increasing worldwide [1,2]
We have shown that apoptosis plays an important role in the local anesthetic-induced cell toxicity of breast cancer cells [15]
Necrosis was observed in high concentrations of lidocaine and bupivacaine. These results suggest that growth suppression by local anesthetics in thyroid cancer cells involves induction of apoptosis
Summary
Thyroid cancer is the most common of all endocrine cancers, and the incidence of thyroid cancer is increasing worldwide [1,2]. The majority of thyroid cancers are well differentiated with papillary and follicular thyroid carcinoma being the most common types. Well-differentiated thyroid cancer has a generally favorable prognosis, the overall recurrence rates could be as high as 35% [3]. Persistent or recurrent disease occurs largely in the neck. Development of recurrence is associated with a higher mortality. Thirty-year cancer mortality rates were reported to be about 12% in patients with local recurrence and 43% in those with distant recurrence [3]
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