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Apoptosis Induced by Local Anesthetics in Tumor Cells
breast cancer,thyroid cancer,local anesthetics,anesthesia,apoptosis,
|Publication Year :||2014|
本研究使用之局部麻醉藥品(Lidocaine, Bupivacaine) 以乳癌腫瘤、甲狀腺癌細胞和利用腫瘤之動物模式，發現其對腫瘤細胞抑制的效果。
另外也發現局部麻醉藥品能抑制甲狀腺癌腫瘤細胞的生存能力，減少細胞群落形成。藉由瓦解粒線體膜電位，釋放细胞色素C (Cytochrome C)，活化凋亡蛋白酶3,7，升高Bax/Bcl-2比例進而引發甲狀腺癌細胞凋亡及壞死。由局部麻醉藥品所誘導之MAPK訊息傳遞路徑可能為其促進細胞凋亡之重要機轉。
The incidence of breast and thyroid cancer has remarkably increased in recent years. Local anesthetics are frequently used in fine-needle aspiration of thyroid lesions and locoregional control of persistent or recurrent thyroid cancer. Wound infiltration with local anesthetics reduces postoperative pain after breast surgery. 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.
We also demonstrated that the apoptotic effects of local anesthetics in human breast tumor cells. Treatment of breast tumor cells with lidocaine and bupivacaine at clinically relevant concentrations resulted in inhibition of cell viability via induction of apoptosis. The effects were more prominent in MCF-7 cells than in MCF-10A cells. Treatment with local anesthetics induced caspase 7, 8, 9, and poly ADP-ribose polymerase (PARP) cleavage. The cleavage of caspase 7 and PARP induced by local anesthetics was effectively blocked by caspase inhibitors. Furthermore, treatment of MCF-7 xenografts with local anesthetics resulted in higher expression of cleaved caspase 7 and an increase in terminal deoxynucleotidyl transferase dUTP nick-end labeling staining.
Our findings reveal previously unrecognized beneficial actions of local anesthetics and call for further studies to assess the oncologic advantages of their use during breast cancer surgery and in the management of patients with thyroid cancer.
|Appears in Collections:||生理學科所|
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