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Anticancer Res. 2014 Apr;34(4):1709-13.

Synergistic inhibition of HCC and liver cancer stem cell proliferation by targeting RAS/RAF/MAPK and WNT/β-catenin pathways.

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1
800 Rose Street, Room C453, Lexington, Kentucky 40536-0293, U.S.A. rgeda2@uky.edu.

Abstract

BACKGROUND/AIM:

The aim of this study is to find synergistic effect using FH535 and sorafenib by targeting the RAS/RAF/MAPK and WNT/β-catenin pathways.

MATERIALS AND METHODS:

3H-Thymidine incorporation assays were performed to address Huh7 and liver cancer stem cell (LCSC) inhibition using FH535 and sorafenib, alone and in combination. Calcusyn analysis was used to calculate the combination index (CI). A western blot assay was performed to check for potential targets.

RESULTS:

FH535 and sorafenib caused inhibition of Huh7 and LCSC. Combination therapy was significantly better than monotherapy in inhibition of HuH7. Combination with sorafenib and FH535 was found to be synergistic in inhibition of LCSC with a CI of less than 1. The western blot assay demonstrated enhanced cleaved poly (ADP-ribose) polymerase (PARP) and inhibition of cyclin D1, B-cell lymphoma 2 (Bcl2), survivin and cellular myelocytomatosis oncogene (c-MYC).

CONCLUSION:

FH535 and sorafenib combination produced synergistic effect on inhibition of HCC and LCSC. Our study demonstrated that FH535 can induce apoptosis in these two different hepatocellular carcinoma (HCC) cell lines.

KEYWORDS:

Hepatocellular carcinoma; PI-103; PKI-587; RAS/RAF/MAPK; epidermal growth factor; liver cancer stem cells; mTOR complex 1; mTOR complex 2; rapamycin; sorafenib

PMID:
24692700
[Indexed for MEDLINE]
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