title: Anti-tumor effect in human lung cancer by a combination treatment of novel histone deacetylase inhibitors: SL142 or SL325 and retinoic acids.
abstract: Histone deacetylase (HDAC) inhibitors arrest cancer cell growth and cause apoptosis with low toxicity thereby constituting a promising treatment for cancer. In this study, we investigated the anti-tumor activity in lung cancer cells of the novel cyclic amide-bearing hydroxamic acid based HDAC inhibitors SL142 and SL325. In A549 and H441 lung cancer cells both SL142 and SL325 induced more cell growth inhibition and cell death than the hydroxamic acid-based HDAC inhibitor suberoylanilide hydroxamic acid (SAHA). Moreover, the combination treatment using retinoid drugs ATRA or 9-cis RA along with SL142 or SL325 significantly induced more apoptosis and suppressed colony formation than the single use of either. The expression of the retinoic acid receptors RARα, RARβ, RXRα and RXRβ were unchanged with the treatment. However a luciferase reporter construct (pGL4. RARE 7x) containing seven tandem repeats of the retinoic acid responsible element (RARE) generated significant transcriptional activity after the combination treatment of retinoic acids and SL142 or SL325 in H441 lung cancer cells. Moreover, apoptosis-promoting Bax expression and caspase-3 activity was increased after the combination treatment. These results suggest that the combination treatment of SL142 or SL325 with retinoic acids exerts significant anti-tumor activity and is a promising therapeutic candidate to treat human lung cancer.
authors.affiliation: Department of Gastroenterological Surgery, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, Okayama, Japan.
authors.forename: Shaoteng
authors.initials: S
authors.lastname: Han
authors.forename: Takuya
authors.initials: T
authors.lastname: Fukazawa
authors.forename: Tomoki
authors.initials: T
authors.lastname: Yamatsuji
authors.forename: Junji
authors.initials: J
authors.lastname: Matsuoka
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Miyachi
authors.forename: Yutaka
authors.initials: Y
authors.lastname: Maeda
authors.forename: Mary
authors.initials: M
authors.lastname: Durbin
authors.forename: Yoshio
authors.initials: Y
authors.lastname: Naomoto
mesh_terms: D000107:Acetylation / Q000187:drug effects; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D053148:Caspase 3 / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D002470:Cell Survival / Q000187:drug effects; D004357:Drug Synergism; D056572:Histone Deacetylase Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D006657:Histones / Q000378:metabolism; D006801:Humans; D006877:Hydroxamic Acids / Q000737:chemistry / Q000494:pharmacology; D015151:Immunoblotting; D054833:Isoindoles / Q000737:chemistry / Q000494:pharmacology; D008175:Lung Neoplasms / Q000378:metabolism / Q000473:pathology; D015394:Molecular Structure; D020218:Response Elements / Q000235:genetics; D014158:Transcription, Genetic / Q000187:drug effects; D014212:Tretinoin / Q000494:pharmacology*; D051028:bcl-2-Associated X Protein / Q000378:metabolism
chemical_list: C557620:3-(2-(4-pyridin-4-yl)benzyl-1-oxoisoindolin-6-yl)-N-hydroxyacrylamide; C557621:3-(2-(4-quinolin-3-yl)benzyl-1-oxoisoindolin-6-yl)-N-hydroxy-acrylamide; D000970:Antineoplastic Agents; C494826:BAX protein, human; D056572:Histone Deacetylase Inhibitors; D006657:Histones; D006877:Hydroxamic Acids; D054833:Isoindoles; D051028:bcl-2-Associated X Protein; D014212:Tretinoin; D053148:Caspase 3