Valproic acid, an antiepileptic drug with histone deacetylase inhibitory activity, potentiates the cytotoxic effect of Apo2L/TRAIL on cultured thoracic cancer cells through mitochondria-dependent caspase activation

M. Firdos Ziauddin, Wen Shuz Yeow, Justin B. Maxhimer, Aris Baras, Alex Chua, Rishindra M. Reddy, Wilson Tsai, George W. Cole, David S. Schrump, Dao M. Nguyen

Research output: Contribution to journalArticle

46 Citations (Scopus)

Abstract

Inhibitors of histone deacetylases have been shown to enhance the sensitivity of cancer cells to tumor necrosis factor-related apoptosis-inducing ligand TRAIL-mediated cytotoxicity. Valproic acid (VA), a commonly used antiepileptic agent whose pharmacokinetics and toxicity profiles are well described, is a histone deacetylase inhibitor. This project aims to evaluate if VA can potentiate Apo2L/TRAIL-mediated cytotoxicity in cultured thoracic cancer cells and to elucidate the underlying molecular mechanism responsible for this effect. VA sensitized cultured thoracic cancer cells to Apo2L/TRAIL, as indicated by a 4-fold to a >20-fold reduction of Apo2L/TRAIL IC50 values in combination-treated cells. Although VA (0.5-5 mM) or Apo2L/TRAIL (20 ng/ml) induced less than 20% cell death, VA + Apo2L/TRAIL combinations caused 60% to 90% apoptosis of cancer cells. Moreover, substantial activation of caspases 8, 9, and 3, which was observed only in cells treated with the drug combinations, was completely suppressed by Bcl2 overexpression or by the caspase 9 inhibitor. Both the caspase 9 inhibitor and Bcl2 completely abrogated the substantial cytotoxicity and apoptosis induced by this combination, thus highlighting the pivotal role of the type II pathway in this process. These findings provide a rationale for the development of VA and Apo2L/TRAIL combination as a novel molecular therapeutic regimen for thoracic cancers.

Original languageEnglish (US)
Pages (from-to)446-457
Number of pages12
JournalNeoplasia
Volume8
Issue number6
DOIs
StatePublished - Jan 1 2006

Fingerprint

Histone Deacetylases
Valproic Acid
Caspases
Anticonvulsants
Mitochondria
Thorax
Caspase 9
Neoplasms
Caspase Inhibitors
Apoptosis
Histone Deacetylase Inhibitors
Caspase 8
Drug Combinations
Caspase 3
Inhibitory Concentration 50
Cell Death
Pharmacokinetics
Tumor Necrosis Factor-alpha
Ligands

Keywords

  • Apo2L/TRAIL
  • Bcl2
  • Caspases
  • Esophageal cancer
  • Histone deacetylase inhibitor
  • Lung cancer
  • Malignant pleural mesothelioma
  • Mitochondria

ASJC Scopus subject areas

  • Cancer Research

Cite this

Valproic acid, an antiepileptic drug with histone deacetylase inhibitory activity, potentiates the cytotoxic effect of Apo2L/TRAIL on cultured thoracic cancer cells through mitochondria-dependent caspase activation. / Ziauddin, M. Firdos; Yeow, Wen Shuz; Maxhimer, Justin B.; Baras, Aris; Chua, Alex; Reddy, Rishindra M.; Tsai, Wilson; Cole, George W.; Schrump, David S.; Nguyen, Dao M.

In: Neoplasia, Vol. 8, No. 6, 01.01.2006, p. 446-457.

Research output: Contribution to journalArticle

Ziauddin, M. Firdos ; Yeow, Wen Shuz ; Maxhimer, Justin B. ; Baras, Aris ; Chua, Alex ; Reddy, Rishindra M. ; Tsai, Wilson ; Cole, George W. ; Schrump, David S. ; Nguyen, Dao M. / Valproic acid, an antiepileptic drug with histone deacetylase inhibitory activity, potentiates the cytotoxic effect of Apo2L/TRAIL on cultured thoracic cancer cells through mitochondria-dependent caspase activation. In: Neoplasia. 2006 ; Vol. 8, No. 6. pp. 446-457.
@article{75061d0c15e045479a011b8395c7343b,
title = "Valproic acid, an antiepileptic drug with histone deacetylase inhibitory activity, potentiates the cytotoxic effect of Apo2L/TRAIL on cultured thoracic cancer cells through mitochondria-dependent caspase activation",
abstract = "Inhibitors of histone deacetylases have been shown to enhance the sensitivity of cancer cells to tumor necrosis factor-related apoptosis-inducing ligand TRAIL-mediated cytotoxicity. Valproic acid (VA), a commonly used antiepileptic agent whose pharmacokinetics and toxicity profiles are well described, is a histone deacetylase inhibitor. This project aims to evaluate if VA can potentiate Apo2L/TRAIL-mediated cytotoxicity in cultured thoracic cancer cells and to elucidate the underlying molecular mechanism responsible for this effect. VA sensitized cultured thoracic cancer cells to Apo2L/TRAIL, as indicated by a 4-fold to a >20-fold reduction of Apo2L/TRAIL IC50 values in combination-treated cells. Although VA (0.5-5 mM) or Apo2L/TRAIL (20 ng/ml) induced less than 20{\%} cell death, VA + Apo2L/TRAIL combinations caused 60{\%} to 90{\%} apoptosis of cancer cells. Moreover, substantial activation of caspases 8, 9, and 3, which was observed only in cells treated with the drug combinations, was completely suppressed by Bcl2 overexpression or by the caspase 9 inhibitor. Both the caspase 9 inhibitor and Bcl2 completely abrogated the substantial cytotoxicity and apoptosis induced by this combination, thus highlighting the pivotal role of the type II pathway in this process. These findings provide a rationale for the development of VA and Apo2L/TRAIL combination as a novel molecular therapeutic regimen for thoracic cancers.",
keywords = "Apo2L/TRAIL, Bcl2, Caspases, Esophageal cancer, Histone deacetylase inhibitor, Lung cancer, Malignant pleural mesothelioma, Mitochondria",
author = "Ziauddin, {M. Firdos} and Yeow, {Wen Shuz} and Maxhimer, {Justin B.} and Aris Baras and Alex Chua and Reddy, {Rishindra M.} and Wilson Tsai and Cole, {George W.} and Schrump, {David S.} and Nguyen, {Dao M.}",
year = "2006",
month = "1",
day = "1",
doi = "10.1593/neo.05823",
language = "English (US)",
volume = "8",
pages = "446--457",
journal = "Neoplasia (United States)",
issn = "1522-8002",
publisher = "Elsevier Inc.",
number = "6",

}

TY - JOUR

T1 - Valproic acid, an antiepileptic drug with histone deacetylase inhibitory activity, potentiates the cytotoxic effect of Apo2L/TRAIL on cultured thoracic cancer cells through mitochondria-dependent caspase activation

AU - Ziauddin, M. Firdos

AU - Yeow, Wen Shuz

AU - Maxhimer, Justin B.

AU - Baras, Aris

AU - Chua, Alex

AU - Reddy, Rishindra M.

AU - Tsai, Wilson

AU - Cole, George W.

AU - Schrump, David S.

AU - Nguyen, Dao M.

PY - 2006/1/1

Y1 - 2006/1/1

N2 - Inhibitors of histone deacetylases have been shown to enhance the sensitivity of cancer cells to tumor necrosis factor-related apoptosis-inducing ligand TRAIL-mediated cytotoxicity. Valproic acid (VA), a commonly used antiepileptic agent whose pharmacokinetics and toxicity profiles are well described, is a histone deacetylase inhibitor. This project aims to evaluate if VA can potentiate Apo2L/TRAIL-mediated cytotoxicity in cultured thoracic cancer cells and to elucidate the underlying molecular mechanism responsible for this effect. VA sensitized cultured thoracic cancer cells to Apo2L/TRAIL, as indicated by a 4-fold to a >20-fold reduction of Apo2L/TRAIL IC50 values in combination-treated cells. Although VA (0.5-5 mM) or Apo2L/TRAIL (20 ng/ml) induced less than 20% cell death, VA + Apo2L/TRAIL combinations caused 60% to 90% apoptosis of cancer cells. Moreover, substantial activation of caspases 8, 9, and 3, which was observed only in cells treated with the drug combinations, was completely suppressed by Bcl2 overexpression or by the caspase 9 inhibitor. Both the caspase 9 inhibitor and Bcl2 completely abrogated the substantial cytotoxicity and apoptosis induced by this combination, thus highlighting the pivotal role of the type II pathway in this process. These findings provide a rationale for the development of VA and Apo2L/TRAIL combination as a novel molecular therapeutic regimen for thoracic cancers.

AB - Inhibitors of histone deacetylases have been shown to enhance the sensitivity of cancer cells to tumor necrosis factor-related apoptosis-inducing ligand TRAIL-mediated cytotoxicity. Valproic acid (VA), a commonly used antiepileptic agent whose pharmacokinetics and toxicity profiles are well described, is a histone deacetylase inhibitor. This project aims to evaluate if VA can potentiate Apo2L/TRAIL-mediated cytotoxicity in cultured thoracic cancer cells and to elucidate the underlying molecular mechanism responsible for this effect. VA sensitized cultured thoracic cancer cells to Apo2L/TRAIL, as indicated by a 4-fold to a >20-fold reduction of Apo2L/TRAIL IC50 values in combination-treated cells. Although VA (0.5-5 mM) or Apo2L/TRAIL (20 ng/ml) induced less than 20% cell death, VA + Apo2L/TRAIL combinations caused 60% to 90% apoptosis of cancer cells. Moreover, substantial activation of caspases 8, 9, and 3, which was observed only in cells treated with the drug combinations, was completely suppressed by Bcl2 overexpression or by the caspase 9 inhibitor. Both the caspase 9 inhibitor and Bcl2 completely abrogated the substantial cytotoxicity and apoptosis induced by this combination, thus highlighting the pivotal role of the type II pathway in this process. These findings provide a rationale for the development of VA and Apo2L/TRAIL combination as a novel molecular therapeutic regimen for thoracic cancers.

KW - Apo2L/TRAIL

KW - Bcl2

KW - Caspases

KW - Esophageal cancer

KW - Histone deacetylase inhibitor

KW - Lung cancer

KW - Malignant pleural mesothelioma

KW - Mitochondria

UR - http://www.scopus.com/inward/record.url?scp=33745822415&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=33745822415&partnerID=8YFLogxK

U2 - 10.1593/neo.05823

DO - 10.1593/neo.05823

M3 - Article

C2 - 16820090

AN - SCOPUS:33745822415

VL - 8

SP - 446

EP - 457

JO - Neoplasia (United States)

JF - Neoplasia (United States)

SN - 1522-8002

IS - 6

ER -