Lidocine potentiates the cytotoxicity of 5‐fluorouracil to choriocarcinoma cells by downregulating ABC transport proteins expression

Abstract

Choriocarcinoma is a gestational trophoblastic cancer, which often occurs in the first 3 months of pregnancy. 5‐Fluorouracil (5‐Fu) is the widely used chemotherapeutic drug for choriocarcinoma but limited by drug resistance. Lidocaine, an aminamide‐type anesthetic, shows potential anticancer and chemosensitization effects in recent years. Herein, we tested the possible chemosensitization activity of lidocaine on the cytotoxicity of 5‐Fu in choriocarcinoma cells. Viabilities and apoptosis of choriocarcinoma JEG‐3 and JAR cells after lidocaine and/or 5‐Fu treatment were detected using Cell Counting Kit‐8 assay, annexin V‐FITC/PI (fluorescein isothiocyanate/propidium iodide) staining and Western blot analysis, respectively. Quantitative reverse transcription polymerase chain reaction was done to measure breast cancer resistance protein (ABCG2) messenger RNA level. Western blot analysis was carried out to detect ABCG2, P‐glycoprotein (P‐gp), MRP1, and MRP2 protein levels. pEX‐ABCG2 was transfected to elevate ABCG2 level. Then, the influence of ABCG2 on lidocaine + 5‐Fu‐caused cell viability loss, apoptosis, and inactivation of PI3K/AKT pathway were analyzed. We found that lidocaine in low concentration had no significant cytotoxicity to JEG‐3 and JAR cells, but stimulated cell apoptosis in high concentration. Moreover, lidocaine potentiated the cytotoxicity of 5‐Fu to JEG‐3 and JAR cells through decreasing viability and increasing apoptosis. Lidocaine treatment reduced the ABCG2, P‐gp, MRP1, and MRP2 protein levels in cells. Overexpression of ABCG2 reversed the synergistic effects of lidocaine + 5‐Fu on JEG‐3 and JAR cell viability and apoptosis, as well as PI3K/AKT pathway. Our research verified that lidocaine potentiated the cytotoxicity of 5‐Fu to choriocarcinoma cells by downregulating ATP‐binding cassette (ABC) transport proteins expression.

Quantitative Proteomic Profiling Identifies SOX8 as Novel Regulator of Drug Resistance in Gestational Trophoblastic Neoplasia

“…Although KEGG pathway analysis revealed differential patterns of pathway activation associated with drug resistance to individual drugs (MTX, 5-Fu, VP16), some common genes/pathways/signaling networks were indeed activated in all the three chemoresistant sublines. Several earlier reports indicated that ABCG2 could confer drug resistance to GTN cells by facilitating drug efflux (10, 34,35). Consistently, increased ABCG2 expression was observed in our drug resistance-related proteomic dataset.…”

Anesthesia Medications and Interaction with Chemotherapeutic Agents

“…When lidocaine was administered in conjunction with 5-FU, JEG-3 and JAR cell line sensitivity to 5-FU was enhanced via increased induction of apoptosis. This study found that lidocaine enhanced the cytotoxic effect of 5-FU to choriocarcinoma cells by reducing resistance via the downregulation of ABC transporter protein expression [68].…”

Local Anesthetic Lidocaine and Cancer: Insight Into Tumor Progression and Recurrence

“…Additionally, lidocaine may induce apoptosis by promoting caspase-3 production by up-regulating the Bax and decreasing of Bcl-2 associating with the signaling pathways of ERK1/2 and p38 ( 22 ). In particular, lidocaine may aggravate the apoptosis through directly inhibited PI3K/AKT/mTOR or influenced AKT/Bcl2/Bax signaling pathway ( 42 , 45 , 46 ). The other effects are related to molecules such as natural killer cells (NK) ( 22 ).…”