Abstract
While cancer treatment has improved dramatically, it has also encountered many critical challenges, such as disease recurrence, metastasis, and drug resistance, making new drugs with novel mechanisms an urgent clinical need. The term “drug repositioning,” also known as old drugs for new uses, has emerged as one practical strategy to develop new anticancer drugs. Anesthetics have been widely used in surgical procedures to reduce the excruciating pain. Lidocaine, one of the most-used local anesthetics in clinical settings, has been found to show multi-activities, including potential in cancer treatment. Growing evidence shows that lidocaine may not only work as a chemosensitizer that sensitizes other conventional chemotherapeutics to certain resistant cancer cells, but also could suppress cancer cells growth by single use at different doses or concentrations. Lidocaine could suppress cancer cell growth in vitro and in vivo via multiple mechanisms, such as regulating epigenetic changes and promoting pro-apoptosis pathways, as well as regulating ABC transporters, metastasis, and angiogenesis, etc., providing valuable information for its further application in cancer treatment and for new drug discovery. In addition, lidocaine is now under clinical trials to treat certain types of cancer. In the current review, we summarize the research and analyze the underlying mechanisms, and address key issues in this area.
Highlights
Cancer treatments have made dramatic progress and achieved tremendous success for the last seven decades as a result of the development of conventional therapies, including surgery, chemotherapy, radiotherapy (DeVita and Chu, 2008), and innovative targeted small-molecule tyrosine kinase inhibitors (Prasad et al, 2016; Lee et al, 2018), as well as the cutting-edge immunotherapy (Macchiarulo, 2017; Harjes, 2018)
Mechanistic studies revealed that lidocaine could suppress the methylation of certain genes, such as retinoic acid receptor β2 (RARβ2) and Ras association domain family 1 isoform A (RASSF1A), two promoters of tumor-suppressive genes. These findings in the present study indicated that, via suppression of RARβ2 and RASSF1A methylation, lidocaine sensitized cisplatin to breast cancer cells (Li et al, 2014)
This study provided interesting information for the reversal of MDR mediated by ABC transporters (Li et al, 2016; Ji et al, 2019) by lidocaine, indicating its ability to reverse the resistance of certain chemotherapeutics that are substrates of ABC transporters and warranting further research
Summary
Cancer treatments have made dramatic progress and achieved tremendous success for the last seven decades as a result of the development of conventional therapies, including surgery, chemotherapy, radiotherapy (DeVita and Chu, 2008), and innovative targeted small-molecule tyrosine kinase inhibitors (Prasad et al, 2016; Lee et al, 2018), as well as the cutting-edge immunotherapy (Macchiarulo, 2017; Harjes, 2018). Another study conducted by Chen et al showed that lidocaine (0.1, 3, and 5 mM, as determined by cell-counting kit-8 reagent) could kill A375 melanoma cells and suppress the colony formation in a concentration-dependent manner via cell cycle arrest at G1 phase (Chen et al, 2019) These effects were mediated by the down-regulation of Ki-67, a protein associated with cell proliferation and the cell division cycle (Robinson et al, 2018; Su and Chen, 2019), and down-regulation of phosphorylation of ERK. Mechanistic studies indicated that lidocaine cut the connections of matrigel and capillary formation, down-regulated vascular endothelial growth factor (VEGF)-activated VEGF receptor 2 (VEGFR2) phosphorylation, phospholipase Cγ (PLCγ)-protein kinase C (PKC)-MAPK, and FAK-paxillin in endothelial cells, leading to the inhibition of angiogenesis and cancer cells migration. A recent study confirmed the suppressing effects of lidocaine to the cell migration, growth, and survival of esophageal carcinoma at >100 μM, which was mediated by inhibiting mitochondrial respiration (Zhu et al, 2020)
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