Tivantinib Decreases Hepatocyte Growth Factor-Induced BCRP Expression in Hepatocellular Carcinoma HepG2 Cells

Area of Science:

• Hepatocellular Carcinoma (HCC) Research
• Molecular Targeted Therapy
• Drug Metabolism and Transport

Background:

• Tivantinib is a cMET inhibitor for HCC, but its monotherapy efficacy is limited.
• The interaction of tivantinib with drug transporters like breast cancer resistance protein (BCRP) and metabolic enzymes like dihydropyrimidine dehydrogenase (DPYD) is not well understood.
• BCRP and DPYD are critical for 5-fluorouracil (5-FU) efficacy in HCC treatment.

Purpose of the Study:

• To investigate the effect of tivantinib on BCRP and DPYD expression in HCC cells.
• To elucidate the regulatory mechanism of tivantinib on BCRP expression.
• To explore the potential for combination therapy of tivantinib and 5-FU in HCC.

Main Methods:

• Hepatocyte growth factor (HGF) and tivantinib treatments on HepG2 cells.
• Quantitative analysis of BCRP and DPYD mRNA levels using real-time RT-PCR.
• Identification of BCRP transcriptional start sites via 5'-RACE.
• Assessment of BCRP promoter activity using dual-luciferase assays.

Main Results:

• HGF upregulated BCRP mRNA levels, but not DPYD, in HepG2 cells.
• Tivantinib reversed HGF-induced BCRP upregulation.
• Tivantinib specifically inhibited BCRP promoter activity upstream of exon 1α, indicating targeted regulation.
• Two transcriptional start sites (E1α, E1β) for BCRP were identified.

Conclusions:

• Tivantinib regulates BCRP expression at the transcriptional level, specifically upstream of BCRP exon 1α.
• The findings support further investigation into combination therapy with tivantinib and 5-FU for HCC.
• Understanding tivantinib's effect on BCRP provides a basis for optimizing HCC treatment strategies.