Sorafenib enhances the chemotherapeutic efficacy of S-1 against hepatocellular carcinoma through downregulation of transcription factor E2F-1.

Abstract

PURPOSE:

Sorafenib and S-1 (one mixed formulation containing 5-FU prodrug and dihydropyrimidine dehydrogenase inhibitor) were two effective agents against hepatocellular carcinoma (HCC), but whether they had synergistic effects remained unclear. The present study aimed at evaluating their synergistic effects against HCC and its mechanisms.

METHODS:

Inhibitory effects of sorafenib, 5-FU and their combination on HCC cells PLC/PRF/5 and SK-HEP-1 were evaluated. Expressions of transcription factor E2F-1 and its downstream thymidylate synthetase (TS) in the treated cells were determined using real-time PCR and Western blot. In vivo anti-tumoral efficacy of S-1 plus sorafenib on HCC was evaluated in NOD/SCID mice. E2F-1 and TS expressions in tumors were determined by immunohistochemical staining.

RESULTS:

Sorafenib inhibited growth of HCC cells in dose-dependent manner, with IC50 of 5.4 ± 0.3 μmol/L for PLC/PRF/5 and 5.3 ± 0.5 μmol/L for SK-HEP-1. Sorafenib (1 μmol/L) enhanced inhibitory efficacy of 5-FU on HCC cells in vitro, dropping IC50 of 5-FU from 167.7 ± 12.1 to 105.4 ± 8.4 μmol/L for PLC/PRF/5 and 115 ± 10.2 to 82 ± 7.4 μmol/L for SK-HEP-1 (both p < 0.01). Sorafenib downregulated E2F-1 and TS expressions on HCC cells, and its combination with 5-FU yielded a synergistic downregulation of TS expression on HCC cells. In NOD/SCID mice with subcutaneously inoculated HCC, sorafenib combined with S-1 yielded greater inhibition on tumor growth and remarkable TS suppression when compared with sorafenib or S-1 alone (all p < 0.05).

CONCLUSIONS:

Sorafenib enhanced therapeutic efficacy of 5-FU/S-1 against HCC through downregulation of E2F-1 and TS expressions. Sorafenib combined with S-1 might represent as valuable therapeutic regimen against HCC.

• Authors: Jing-Ming Zhai, Xiao-Yu Yin, Ying-Rong Lai, Xun Hou, Jian-Peng Cai, Xiao-Yi Hao, Li-Jian Liang, Long-Juan Zhang
• Journal: Cancer chemotherapy and pharmacology (Cancer Chemother Pharmacol) Vol. 71 Issue 5 Pg. 1255-64 (May 2013) ISSN: 1432-0843 [Electronic] Germany
• PMID: 23435877 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Drug Combinations
• E2F1 Transcription Factor
• E2f1 protein, mouse
• Phenylurea Compounds
• S 1 (combination)
• Tegafur
• Niacinamide
• Oxonic Acid
• Sorafenib
• Thymidylate Synthase

Topics

• Animals
• Antineoplastic Combined Chemotherapy Protocols (administration & dosage, pharmacology)
• Blotting, Western
• Carcinoma, Hepatocellular (drug therapy, genetics, pathology)
• Cell Line, Tumor
• Dose-Response Relationship, Drug
• Down-Regulation (drug effects)
• Drug Combinations
• Drug Synergism
• E2F1 Transcription Factor (genetics)
• Gene Expression Regulation, Neoplastic (drug effects)
• Humans
• Inhibitory Concentration 50
• Liver Neoplasms (drug therapy, genetics, pathology)
• Male
• Mice
• Mice, Inbred NOD
• Mice, SCID
• Niacinamide (administration & dosage, analogs & derivatives)
• Oxonic Acid (administration & dosage)
• Phenylurea Compounds (administration & dosage)
• Real-Time Polymerase Chain Reaction
• Sorafenib
• Tegafur (administration & dosage)
• Thymidylate Synthase (genetics)