Potentiation of the anticancer effect of valproic acid, an antiepileptic agent with histone deacetylase inhibitory activity, by the kinase inhibitor Staurosporine or its clinically relevant analogue UCN-01

W. S. Yeow, M. F. Ziauddin, J. B. Maxhimer, S. Shamimi-Noori, A. Baras, A. Chua, D. S. Schrump, Dao Nguyen

Research output: Contribution to journalArticle

40 Citations (Scopus)

Abstract

Histone deacetylase inhibitors (HDACls) are novel anticancer agents with potent cytotoxicity against a wide range of malignancies. We have previously demonstrated that either Calphostin C (CC) (a protein kinase C (PKC) inhibitor) or Parthenolide (an NF-κB inhibitor) abrogates HDACl-induced transcriptional activation of NF-κB and p21, which is associated with profound potentiation of HDACl-mediated induction of apoptosis. Valproic acid (VA), a commonly used antiepileptic agent, has recently been shown to be an HDACl. This study was aimed to evaluate the anticancer property of VA in thoracic cancer cells and the development of clinically relevant strategies to enhance VA-mediated induction of apoptosis using kinase inhibitors Staurosporine (STP) or its analogue UCN-01. Treating cultured thoracic cancer cells with VA (0.62-10.0 mM) resulted in significant cell line- and dose-dependent growth inhibition (IC50 values: 4.1-6.0 mM) and cell cycle arrest at G1/S checkpoint with profound accumulation of cells at G0/G1 phase but little induction of apoptosis. Valproic acid, being an HDACl, caused significant dose-dependent accumulation of hyperacetylated histones, following 24 h of treatment. Valproic acid-mediated 5-20-fold upregulation of transcriptional activity of NF-κB was substantially (50-90%) suppressed by cotreatment with CC, STP or UCN-01. Whereas minimal death (<20%) was observed in cells treated with either VA (1.0 or 5.0 mM) alone or kinase inhibitors alone, 60-90% of cells underwent apoptosis following exposure to combinations of VA + kinase inhibitors. Kinase inhibitor-mediated suppression of NF-κB transcriptional activity played an important role in sensitising cancer cells to VA as direct inhibition of NF-κB by Parthenolide drastically synergised with VA to induce apoptosis (VA + Parthenolide: 60-90% compared to <20% following single-drug treatments). In conclusion, VA, a well-known antiepileptic drug, has mild growth-inhibitory activity on cultured cancer cells. The weak VA-mediated induction of apoptosis of thoracic cancer cells can be profoundly enhanced either by Parthenolide, a pharmacologic inhibitor of NF-κB, or by UCN-10 a kinase inhibitor that has already undergone phase I clinical development. Combinations of VA with either a PKC inhibitor or an NF-κB inhibitor are promising novel molecularly targeted therapeutics for thoracic cancers.

Original languageEnglish
Pages (from-to)1436-1445
Number of pages10
JournalBritish Journal of Cancer
Volume94
Issue number10
DOIs
StatePublished - May 22 2006
Externally publishedYes

Fingerprint

Histone Deacetylases
Staurosporine
Valproic Acid
Anticonvulsants
Phosphotransferases
Histone Deacetylase Inhibitors
Apoptosis
Thorax
Neoplasms
Protein C Inhibitor
Protein Kinase Inhibitors
7-hydroxystaurosporine
Protein Kinase C
G1 Phase Cell Cycle Checkpoints
Cell Cycle Resting Phase
G1 Phase
Growth
Antineoplastic Agents
Histones
Transcriptional Activation

Keywords

  • Apoptosis
  • Histone deacetylase inhibitor
  • NF-κB
  • Parthenolide
  • Protein kinase C
  • Staurosporine
  • UCN-01
  • Valproic acid

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Potentiation of the anticancer effect of valproic acid, an antiepileptic agent with histone deacetylase inhibitory activity, by the kinase inhibitor Staurosporine or its clinically relevant analogue UCN-01. / Yeow, W. S.; Ziauddin, M. F.; Maxhimer, J. B.; Shamimi-Noori, S.; Baras, A.; Chua, A.; Schrump, D. S.; Nguyen, Dao.

In: British Journal of Cancer, Vol. 94, No. 10, 22.05.2006, p. 1436-1445.

Research output: Contribution to journalArticle

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abstract = "Histone deacetylase inhibitors (HDACls) are novel anticancer agents with potent cytotoxicity against a wide range of malignancies. We have previously demonstrated that either Calphostin C (CC) (a protein kinase C (PKC) inhibitor) or Parthenolide (an NF-κB inhibitor) abrogates HDACl-induced transcriptional activation of NF-κB and p21, which is associated with profound potentiation of HDACl-mediated induction of apoptosis. Valproic acid (VA), a commonly used antiepileptic agent, has recently been shown to be an HDACl. This study was aimed to evaluate the anticancer property of VA in thoracic cancer cells and the development of clinically relevant strategies to enhance VA-mediated induction of apoptosis using kinase inhibitors Staurosporine (STP) or its analogue UCN-01. Treating cultured thoracic cancer cells with VA (0.62-10.0 mM) resulted in significant cell line- and dose-dependent growth inhibition (IC50 values: 4.1-6.0 mM) and cell cycle arrest at G1/S checkpoint with profound accumulation of cells at G0/G1 phase but little induction of apoptosis. Valproic acid, being an HDACl, caused significant dose-dependent accumulation of hyperacetylated histones, following 24 h of treatment. Valproic acid-mediated 5-20-fold upregulation of transcriptional activity of NF-κB was substantially (50-90{\%}) suppressed by cotreatment with CC, STP or UCN-01. Whereas minimal death (<20{\%}) was observed in cells treated with either VA (1.0 or 5.0 mM) alone or kinase inhibitors alone, 60-90{\%} of cells underwent apoptosis following exposure to combinations of VA + kinase inhibitors. Kinase inhibitor-mediated suppression of NF-κB transcriptional activity played an important role in sensitising cancer cells to VA as direct inhibition of NF-κB by Parthenolide drastically synergised with VA to induce apoptosis (VA + Parthenolide: 60-90{\%} compared to <20{\%} following single-drug treatments). In conclusion, VA, a well-known antiepileptic drug, has mild growth-inhibitory activity on cultured cancer cells. The weak VA-mediated induction of apoptosis of thoracic cancer cells can be profoundly enhanced either by Parthenolide, a pharmacologic inhibitor of NF-κB, or by UCN-10 a kinase inhibitor that has already undergone phase I clinical development. Combinations of VA with either a PKC inhibitor or an NF-κB inhibitor are promising novel molecularly targeted therapeutics for thoracic cancers.",
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AU - Yeow, W. S.

AU - Ziauddin, M. F.

AU - Maxhimer, J. B.

AU - Shamimi-Noori, S.

AU - Baras, A.

AU - Chua, A.

AU - Schrump, D. S.

AU - Nguyen, Dao

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