Alendronate and FTI-277 combination as a possible therapeutic approach for hepatocellular carcinoma: An in vitro study.

Abstract

BACKGROUND:

An important product of mevalonate pathway is downstream synthesis of isoprenoid units that has long been implicated in development and progression of tumor. It has been speculated that inhibition of protein prenylation might be therapeutically beneficial. The objective of current study was to evaluate antitumor potential of a novel therapeutic combination of mevalonate pathway inhibitors, FTI-277 and alendronate. We also examined differentially expressed proteins in response to treatment using proteomics approach.

METHODS:

Huh-7 cells were incubated with different concentrations of FTI-277 alone and in combination with alendronate. Differential protein and gene expression was examined through two dimensional gel electrophoresis and real-time quantitative polymerase chain reaction (qPCR), respectively. Proteins were identified using tandem mass spectrometry analysis.

RESULTS:

Treatment of hepatocellular carcinoma (HCC) cell line with FTI-277 alone showed cell death in a time and dose dependent manner while in combination with alendronate, a synergistic apoptotic effect at 24 h was observed. Proteomic studies on the 20 µmol/L FTI-277 and 5 µmol/L alendronate +20 µmol/L FTI-277 treated cells revealed altered expression of different proteins including peroxiredoxin 2 (Prx2), glutathione S transferase 1 (GSTP1), Rho GTPase activating protein (RhoGAP), triosephosphate isomerase (TPI), and heat shock protein 60 (HSP60). Down-regulated expression of Prx2 and GSTP1 in treated cells was also confirmed by real-time qPCR analysis.

CONCLUSIONS:

Combined treatment of FTI-277 and alendronate on Huh-7 HCC cells showed cell death suggesting their anticancer potential. Such treatment approaches are likely to offer new therapeutic strategies.

• Authors: Amber Ilyas, Zehra Hashim, Iffat Saeed Channa, Shamshad Zarina
• Journal: Hepatobiliary & pancreatic diseases international : HBPD INT (Hepatobiliary Pancreat Dis Int) Vol. 17 Issue 3 Pg. 241-250 (Jun 2018) ISSN: 1499-3872 [Print] Singapore
• PMID: 29627155 (Publication Type: Journal Article)
• Copyright: Copyright © 2018 First Affiliated Hospital, Zhejiang University School of Medicine in China. Published by Elsevier B.V. All rights reserved.

Chemical References

• Biomarkers, Tumor
• FTI 277
• Methionine
• Alendronate

Topics

• Alendronate (pharmacology)
• Antineoplastic Combined Chemotherapy Protocols (pharmacology)
• Apoptosis (drug effects)
• Biomarkers, Tumor (genetics, metabolism)
• Carcinoma, Hepatocellular (drug therapy, genetics, metabolism, pathology)
• Cell Line, Tumor
• Dose-Response Relationship, Drug
• Electrophoresis, Gel, Two-Dimensional
• Gene Expression Regulation, Neoplastic (drug effects)
• Humans
• Inhibitory Concentration 50
• Liver Neoplasms (drug therapy, genetics, metabolism, pathology)
• Methionine (analogs & derivatives, pharmacology)
• Proteomics (methods)
• Signal Transduction (drug effects)
• Tandem Mass Spectrometry
• Time Factors