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.
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-kappaB inhibitor) abrogates HDACI-induced transcriptional activation of NF-kappaB 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 mM) resulted in significant cell line- and dose-dependent growth inhibition (IC(50) 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 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-kappaB 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-kappaB transcriptional activity played an important role in sensitising cancer cells to VA as direct inhibition of NF-kappaB 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-kappaB, or by UCN-01 a kinase inhibitor that has already undergone phase I clinical development. Combinations of VA with either a PKC inhibitor or an NF-kappaB inhibitor are promising novel molecularly targeted therapeutics for thoracic cancers.
Yeow
W-S
WS
Section of Thoracic Oncology, Surgery Branch, Center for Cancer Research, NCI, NIH, Bethesda, MD 20892, USA.
Ziauddin
M F
MF
Maxhimer
J B
JB
Shamimi-Noori
S
S
Baras
A
A
Chua
A
A
Schrump
D S
DS
Nguyen
D M
DM
D000927:Anticonvulsants / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D056572:Histone Deacetylase Inhibitors; D006801:Humans; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism; D009369:Neoplasms / Q000188:drug therapy* / Q000473:pathology; D019311:Staurosporine / Q000031:analogs & derivatives* / Q000494:pharmacology*; D014407:Tumor Cells, Cultured; D014635:Valproic Acid / Q000494:pharmacology*
D000927:Anticonvulsants; D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D056572:Histone Deacetylase Inhibitors; D016328:NF-kappa B; D014635:Valproic Acid; C054852:7-hydroxystaurosporine; D019311:Staurosporine