title: Antitumor effect of the histone deacetylase inhibitor LAQ824 in combination with 13-cis-retinoic acid in human malignant melanoma.
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 beta (RARbeta). 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 RARbeta2 gene expression was associated with histone acetylation and gene methylation at the promoter level. Treatment with LAQ824 restored retinoid sensitivity by reverting RARbeta2 epigenetic silencing. The biological effect of LAQ824 was associated with p21 induction in both cell lines but G(2) 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% and 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 HDAC inhibitor LAQ824 has a greater antitumor activity in 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.
authors.affiliation: The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Johns Hopkins School of Medicine, Bunting-Blaustein Cancer Research Building 1M52, 1650 Orleans Street, Baltimore, Maryland, MD 21231, USA.
authors.forename: Yukihiko
authors.initials: Y
authors.lastname: Kato
authors.forename: Brenda C
authors.initials: BC
authors.lastname: Salumbides
authors.forename: Xiao-Fei
authors.initials: XF
authors.lastname: Wang
authors.forename: David Z
authors.initials: DZ
authors.lastname: Qian
authors.forename: Simon
authors.initials: S
authors.lastname: Williams
authors.forename: Yongfeng
authors.initials: Y
authors.lastname: Wei
authors.forename: Tolib B
authors.initials: TB
authors.lastname: Sanni
authors.forename: Peter
authors.initials: P
authors.lastname: Atadja
authors.forename: Roberto
authors.initials: R
authors.lastname: Pili
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology* / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000235:genetics / Q000378:metabolism; D016195:G2 Phase / Q000187:drug effects; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D056572:Histone Deacetylase Inhibitors; D006801:Humans; D006877:Hydroxamic Acids / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use; D015474:Isotretinoin / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use; D008297:Male; D008545:Melanoma / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D051379:Mice; D008819:Mice, Nude; D008840:Microfilament Proteins / Q000235:genetics; D009124:Muscle Proteins / Q000235:genetics; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D018168:Receptors, Retinoic Acid / Q000235:genetics
chemical_list: D000970:Antineoplastic Agents; D050759:Cyclin-Dependent Kinase Inhibitor p21; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; C477361:LAQ824; D008840:Microfilament Proteins; D009124:Muscle Proteins; D012333:RNA, Messenger; D017382:Reactive Oxygen Species; D018168:Receptors, Retinoic Acid; C082925:retinoic acid receptor beta; C051615:transgelin; D015474:Isotretinoin