Local anesthetic lidocaine induces growth suppression of HeLa cells by decreasing and changing the cellular localization of the proliferation marker Ki‐67

Abstract

Although surgery is a basic therapy for cancer, it causes inflammation and immunosuppression, often resulting in recurrence and metastasis. Previous studies have suggested that anesthetic management influences the prognosis of cancer surgery patients. Administration of local anesthetics, such as lidocaine, for pain control reportedly improves their clinical outcomes; however, the precise underlying mechanism has not been fully elucidated. The growth of human embryonic kidney (HEK) 293T and cervical cancer HeLa cells was inhibited by lidocaine treatment and these cell lines showed different sensitivities for lidocaine. Ki-67 is a significant prognostic marker of cancer because it is expressed in the nucleus of actively proliferating cells. In lidocaine-treated HeLa cells, Ki-67 was detected not only in the nucleus but also in the cytoplasm. In addition, lidocaine-induced cytoplasmic Ki-67 partly colocalized with the increased ER chaperone, glucose-regulated protein 78, which is crucial for protein folding and maintenance of cellular homeostasis. Furthermore, lidocaine decreased Ki-67 levels and increased the population of HeLa cells in the G0/G1 phase. These results indicate that lidocaine plays a significant role in growth suppression by regulating the expression and distribution of Ki-67.

Voltage-Gated Sodium Channel NaV1.7 Inhibitors with Potent Anticancer Activities in Medullary Thyroid Cancer Cells

“…From this cell cycle analysis, levobupivacaine and chloroprocaine slightly activated cell cycle arrest at the S phase, while ropivacaine remarkably induced cell cycle arrest at the G2/M phase [90]. Interestingly, lidocaine, a VGSC inhibitor that was reported to decrease cell proliferation and reduce cancer cells' migration and invasion [64,91,92], showed a mild effect on cell cycle arrest at the S phase, with no significant influence on the migration of MDA-MB-231 cells at its antiarrhythmic plasma concentration (10 µM) after 24 h of treatment [90]. Additionally, the treatment of lidocaine at 100 µM was reported to inhibit cell growth at 72 h and increase apoptosis at 48 h; however, it did not show a significant effect on cell cycle arrest in hepatocellular carcinoma HuH7 and HepaRG cells (both cell lines had no report of VGSCs' expression) [93].…”

“…Additionally, the treatment of lidocaine at 100 µM was reported to inhibit cell growth at 72 h and increase apoptosis at 48 h; however, it did not show a significant effect on cell cycle arrest in hepatocellular carcinoma HuH7 and HepaRG cells (both cell lines had no report of VGSCs' expression) [93]. A recent study on the treatment of lidocaine in cervical cancer HeLa cells that expressed Na V 1.6 [65] found that this drug significantly inhibited the cell growth at 0.3 mM by reducing a proliferating protein, Ki-67 (MKI67), and a cell cycle analysis indicated that lidocaine significantly induced arrest at the G0/G1 phase and decreased cells' population at the G/M and S phases in a dose-dependent manner [91]. In addition, the knockdown of Na V 1.5 in oral squamous cell carcinoma (OSCC) HSC-3 cells caused cell cycle arrest at the G1 phase and a drastic reduction in cell migration and invasion [94].…”

“…cycle analysis indicated that lidocaine significantly induced arrest at the G0/G1 phase and decreased cells' population at the G/M and S phases in a dose-dependent manner [91]. In addition, the knockdown of NaV1.5 in oral squamous cell carcinoma (OSCC) HSC-3 cells caused cell cycle arrest at the G1 phase and a drastic reduction in cell migration and invasion [94].…”

Trial watch: local anesthetics in cancer therapy

“…LAs also exhibit short-term cytostatic and long-term cytotoxic properties. 27 Interestingly, the chemical structure (ester or amide) does not seem to dictate cytotoxicity activity, whereas it is worth noting that chloroprocaine and prilocaine, which possess a short duration of action, induce fewer effects on cancer cells than agents with an extended time of efficacy. 28 Among the tested LAs, bupivacaine appears to be the most cytotoxic, while procaine is the least.…”