Abstract
Background/Aims: There are limited chemotherapy options for hepatocellular carcinoma (HCC). The heparin-degrading endosulfatase SULF1 functions as a liver tumor suppressor. We investigated the effects of the histone deacetylase inhibitor apicidin in combination with doxorubicin in SULF1-expressing HCC cells in vitro and in SULF1-expressing xenografts in nude mice. Methods: We evaluated the effects of apicidin alone or combined with doxorubicin on apoptosis, caspase activity, and phosphorylation of Erk and Akt in SULF1-transfected Huh7 and Hep3B cells in vitro and in vivo. Results: Apicidin induced HCC cell apoptosis and caspase activation in a dose- and time-dependent manner. Apicidin-induced caspase activation was significantly inhibited by the caspase inhibitor Z-Vad-fmk. Apicidin also decreased phosphorylation of both Erk and Akt. Expression of constitutively-active Mek1 and Akt significantly decreased apicidin-induced apoptosis. The combination of doxorubicin with apicidin significantly increased the anti-tumor effect in the SULF1-expressing Huh7 and Hep3B cells as compared to either apicidin or doxorubicin alone, both in vitro and in vivo. Conclusions: The combination of a histone deacetylase inhibitor with doxorubicin may be a novel and promising therapeutic modality for HCCs, particularly for SULF1-expressing HCCs.
Original language | English (US) |
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Pages (from-to) | 1112-1121 |
Number of pages | 10 |
Journal | Journal of hepatology |
Volume | 50 |
Issue number | 6 |
DOIs | |
State | Published - Jun 2009 |
Keywords
- Akt kinase
- Apoptosis
- Doxorubicin
- Hepatocellular carcinoma
- Histone deacetylase inhibitor
- MAP kinase
- Sulfatase 1 (SULF1)
ASJC Scopus subject areas
- Hepatology