Additive effect of apicidin and doxorubicin in sulfatase 1 expressing hepatocellular carcinoma in vitro and in vivo

Jin Ping Lai, Dalbir S. Sandhu, Catherine D. Moser, Sophie C. Cazanave, Abdul M. Oseini, Abdirashid M. Shire, Vijayalakshmi Shridhar, Schuyler O. Sanderson, Lewis Rowland Roberts

Research output: Contribution to journalArticle

25 Citations (Scopus)

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 languageEnglish (US)
Pages (from-to)1112-1121
Number of pages10
JournalJournal of Hepatology
Volume50
Issue number6
DOIs
StatePublished - Jun 2009

Fingerprint

Sulfatases
Doxorubicin
Hepatocellular Carcinoma
Caspases
Histone Deacetylase Inhibitors
Apoptosis
Phosphorylation
Caspase Inhibitors
In Vitro Techniques
apicidin
Heterografts
Nude Mice
Heparin
Neoplasms
Drug Therapy
Liver

Keywords

  • Akt kinase
  • Apoptosis
  • Doxorubicin
  • Hepatocellular carcinoma
  • Histone deacetylase inhibitor
  • MAP kinase
  • Sulfatase 1 (SULF1)

ASJC Scopus subject areas

  • Hepatology

Cite this

Additive effect of apicidin and doxorubicin in sulfatase 1 expressing hepatocellular carcinoma in vitro and in vivo. / Lai, Jin Ping; Sandhu, Dalbir S.; Moser, Catherine D.; Cazanave, Sophie C.; Oseini, Abdul M.; Shire, Abdirashid M.; Shridhar, Vijayalakshmi; Sanderson, Schuyler O.; Roberts, Lewis Rowland.

In: Journal of Hepatology, Vol. 50, No. 6, 06.2009, p. 1112-1121.

Research output: Contribution to journalArticle

Lai, Jin Ping ; Sandhu, Dalbir S. ; Moser, Catherine D. ; Cazanave, Sophie C. ; Oseini, Abdul M. ; Shire, Abdirashid M. ; Shridhar, Vijayalakshmi ; Sanderson, Schuyler O. ; Roberts, Lewis Rowland. / Additive effect of apicidin and doxorubicin in sulfatase 1 expressing hepatocellular carcinoma in vitro and in vivo. In: Journal of Hepatology. 2009 ; Vol. 50, No. 6. pp. 1112-1121.
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AU - Sandhu, Dalbir S.

AU - Moser, Catherine D.

AU - Cazanave, Sophie C.

AU - Oseini, Abdul M.

AU - Shire, Abdirashid M.

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AU - Roberts, Lewis Rowland

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AB - 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.

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