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

• Published in: British journal of cancer 2006-05, Vol.94 (10), p.1436-1445
• Main Authors: Yeow, W-S, Ziauddin, M F, Maxhimer, J B, Shamimi-Noori, S, Baras, A, Chua, A, Schrump, D S, Nguyen, D M
• Format: Article
• Language: English
• Subjects: Anticonvulsants - pharmacology; Antineoplastic Agents - pharmacology; Apoptosis - drug effects; Biological and medical sciences; Biomedical and Life Sciences; Biomedicine; Cancer Research; Dose-Response Relationship, Drug; Drug Resistance; Drug Synergism; Enzyme Inhibitors - pharmacology; Epidemiology; Histone Deacetylase Inhibitors; Humans; Medical sciences; Molecular Medicine; Neoplasms - drug therapy; Neoplasms - pathology; NF-kappa B - genetics; NF-kappa B - metabolism; Oncology; Staurosporine - analogs & derivatives; Staurosporine - pharmacology; Translational Therapeutics; Tumor Cells, Cultured; Tumors; Valproic Acid - pharmacology
• ISSN: 0007-0920; 1532-1827
• DOI: 10.1038/sj.bjc.6603132

Histone deacetylase inhibitors (HDACIs) 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- κ B inhibitor) abrogates HDACI-induced transcriptional activation of NF- κ B and p21, which is associated with profound potentiation of HDACI-mediated induction of apoptosis. Valproic acid (VA), a commonly used antiepileptic agent, has recently been shown to be an HDACI. 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 m M ) resulted in significant cell line- and dose-dependent growth inhibition (IC 50 values: 4.1–6.0 m M ) 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 HDACI, 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- κ B was substantially (50–90%) suppressed by cotreatment with CC, STP or UCN-01. Whereas minimal death (