Lidocaine inhibits melanoma cell proliferation by regulating ERK phosphorylation

Abstract

The melanoma is responsible for the majority of all skin cancer–related deaths worldwide. Evidence suggests that local anesthetics provide some benefit in the treatment of cancer via inhibition of cellular proliferation, invasion and migration. However, the potential antiproliferative effects of local anesthetics in the treatment of melanoma remain to be elucidated. In this study, we investigated the antiproliferative effects and underlying mechanism of the commonly used local anesthetic (lidocaine) on melanoma cells. A375 melanoma cells were treated by lidocaine or vemurafenib. Cell Counting Kit‐8, histological staining, flow cytometric analysis, immunohistochemical staining, and Western blot analyses were carried out to test the effects of lidocaine and vemurafenib on A375 cells. BALB/C‐nu/nu mice intraperitoneally injected with A375 cells were treated by lidocaine, and then tumor volume and weight were calculated. Lidocaine exhibited vemurafenib‐like effects totally. Lidocaine inhibited A375 melanoma cell proliferation in a dose‐ and time‐dependent manner and colony formation also showed a dose‐dependent inhibition. Lidocaine treatment resulted in the arrest of cell‐cycle progression in the G1 phase and inhibited Ki‐67 expression in a dose‐dependent manner. This effect was associated with inhibited extracellular signal–regulated kinase (ERK) phosphorylation. In vivo experiments revealed that intravenous injections of lidocaine suppressed tumor volume and weight. Lidocaine inhibits melanoma cell proliferation in a dose‐ and time‐dependent manner via a mechanism that may involve inhibition of the ERK signaling pathway. Thus, lidocaine may provide some benefit for the treatment of melanoma.

Lidocaine inhibits proliferation and metastasis of lung cancer cell via regulation of miR-539/EGFR axis

“…These two signalling pathways are also in charge of the growth and metastasis of human cancers, including lung cancer [32]. The inhibitory effects of lidocaine on the activation of ERK and PI3K/AKT pathways have been found in melanoma cells [26,33]. However, only one literature indicated the effects of lidocaine on PI3K/AKT signalling in lung cancer cells [13].…”

Repositioning Lidocaine as an Anticancer Drug: The Role Beyond Anesthesia

“…Although the anticancer efficacies can be confirmed in various cancers, its exact mechanisms/targets remain unclear. As summarized in Table 1 and Figure 2 , the reported targets/mechanisms include MMP-9 ( Piegeler et al, 2015 ), ERK ( Chen et al, 2019 ), TRPV6 ( Jiang et al, 2016 ), and VEGF/VEGFR2 ( Gao et al, 2019 ), as well as the regulation of epigenetics ( Li et al, 2014 ), mi-RNA ( Qu et al, 2018 ; Sui et al, 2019 ; Yang Q. et al, 2019 ), inhibition of metastasis ( D’Agostino et al, 2018 ; Johnson et al, 2018 ; Sun and Sun, 2019 ), inhibition of inflammation ( Freeman et al, 2019 ), impacting mitochondrial metabolism ( Okamoto et al, 2017 ; Gong et al, 2018 ), the regulation of reactive oxygen species (ROS) ( Okamoto et al, 2016 ), etc. Importantly, as an ion channel regulator, lidocaine may exert its anticancer effects via regulation of other channels or membrane potential, such as mitochondrial membrane potential (MMP), which may lead to the decrease of MMP, finally resulting in the mitochondria-related apoptosis ( Li et al, 2014 ; Lu et al, 2016 ; Ye L. et al, 2019 ), providing valuable information for its targets identification.…”

“…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.…”

A clinical mini-review: Clinical use of Local anesthetics in cancer surgeries

“…Many preclinical studies also revealed the mechanism underlying the effects of local anesthetics on cancer cells [6]. Several pathways were reported to be involved in the effect of local anesthetics on cancer cells, including the Wnt/βcatenin pathway [7], the apoptosis pathway [8], the MAPK/ERK pathway [9,10], REDOX pathway [11], RhoA/ROCK/ MLC pathway [12] and so on. Certain growth factors [13] or regulating molecular [14] were also through to be targeted by lidocaine.…”