Antitumor effect of the histone deacetylase inhibitor LAQ824 in combination with 13-cis-retinoic acid in human malignant melanoma

Yukihiko Kato, Brenda C. Salumbides, Xiao Fei Wang, Zheng (David) Qian, Simon Williams, Yongfeng Wei, Tolib B. Sanni, Peter Atadja, Roberto Pili

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Abstract

Resistance to chemotherapy is a major hurdle in the treatment of malignant melanoma. Histone deacetylase (HDAC) inhibitors have been shown to have antitumor activity in different tumor types, including melanoma, and to reverse epigenetic repression of tumor suppressor genes, such as retinoic acid receptor,β (RARβ). In this study, we tested the antitumor effect of the HDAC inhibitor LAQ824 in combination with 13-cis-retinoic acid (CRA) on two human melanoma cell lines both in vitro and in vivo. Treatment of LAQ824 showed a dose-dependent inhibitory effect on A2058 and HMV-I cell lines in a clonogenic assay. These cell lines were relatively resistance to CRA. On treatment with combination of LAQ824 and CRA, a greater inhibitory effect (up to 98%) was achieved compared with single agents. Lack of RARβ2 gene expression was associated with histone acetylation and gene methylation at the promoter level. Treatment with LAQ824 restored retinoid sensitivity by reverting RARβ2 epigenetic silencing. The biological effect of LAQ824 was associated with p21 induction in both cell lines but G2 cell cycle arrest in A2058 and apoptosis in HMV-I cell line. The induction of apoptosis by LAQ824 was associated with increased reactive oxygen species and induction of SM22 gene expression in HMV-I but not in A2058 cell line. Administration of the free radical scavenger L-N-acetylcysteine blocked LAQ824 + CRA-mediated apoptosis in HMV-I cells, suggesting a primary role for reactive oxygen species generation in LAQ824 + CRA - associated lethality. Combination treatment showed 61% an d 82% growth inhibition in A2058 and HMV-I tumors, respectively. Greater induction of in vivo apoptosis was observed in the HMV-I but not in the A2058 tumors treated with combination therapy compared with single agents. These results suggest that the combination with CRA in melanoma tumors but the degree of induced apoptosis may vary. Combination of HDAC inhibitors and retinoids represents a novel therapeutic approach for malignant melanoma that warrants clinical testing.

Original languageEnglish (US)
Pages (from-to)70-81
Number of pages12
JournalMolecular Cancer Therapeutics
Volume6
Issue number1
DOIs
StatePublished - Jan 2007
Externally publishedYes

Fingerprint

NSC 153174
Isotretinoin
Histone Deacetylase Inhibitors
Melanoma
Tretinoin
Cell Line
Apoptosis
Retinoids
Epigenetic Repression
Reactive Oxygen Species
Neoplasms
Therapeutics
G2 Phase Cell Cycle Checkpoints
Gene Expression
Free Radical Scavengers
Retinoic Acid Receptors
LAQ824
Acetylcysteine
Acetylation
Tumor Suppressor Genes

ASJC Scopus subject areas

  • Oncology
  • Drug Discovery
  • Pharmacology

Cite this

Antitumor effect of the histone deacetylase inhibitor LAQ824 in combination with 13-cis-retinoic acid in human malignant melanoma. / Kato, Yukihiko; Salumbides, Brenda C.; Wang, Xiao Fei; Qian, Zheng (David); Williams, Simon; Wei, Yongfeng; Sanni, Tolib B.; Atadja, Peter; Pili, Roberto.

In: Molecular Cancer Therapeutics, Vol. 6, No. 1, 01.2007, p. 70-81.

Research output: Contribution to journalArticle

Kato, Yukihiko ; Salumbides, Brenda C. ; Wang, Xiao Fei ; Qian, Zheng (David) ; Williams, Simon ; Wei, Yongfeng ; Sanni, Tolib B. ; Atadja, Peter ; Pili, Roberto. / Antitumor effect of the histone deacetylase inhibitor LAQ824 in combination with 13-cis-retinoic acid in human malignant melanoma. In: Molecular Cancer Therapeutics. 2007 ; Vol. 6, No. 1. pp. 70-81.
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