title: Multi-targeted DATS prevents tumor progression and promotes apoptosis in ectopic glioblastoma xenografts in SCID mice via HDAC inhibition.
abstract: Glioblastoma, the most lethal brain tumor, remains incurable despite aggressive chemotherapy and surgical interventions. New chemotherapeutics for glioblastoma have been explored in preclinical models and some agents have reached the clinical setting. However, success rates are not significant. Previous investigations involving diallyl trisulfide (DATS), a garlic compound, indicated significant anti-cancer effects in glioblastoma in vitro. DATS has also been shown to inhibit histone deacetylase activity and impede glioblastoma tumor progression. We hypothesized that DATS would block ectopic U87MG tumor by multiple pro-apoptotic pathways via inhibiting histone deacetylase (HDAC). To prove this, we developed ectopic U87MG tumors in SCID mice and treated them daily with intraperitoneal injections of DATS for 7 days. Results indicated that DATS (10 μg/kg-10 mg/kg) dose-dependently reduced tumor mass and number of mitotic cells within tumors. Histological and biochemical assays demonstrated that DATS reduced mitosis in tumors, decreased HDAC activity, increased acetylation of H3 and H4, inhibited cell cycle progression, decreased pro-tumor markers (e.g., survivin, Bcl-2, c-Myc, mTOR, EGFR, VEGF), promoted apoptotic factors (e.g., bax, mcalpian, active caspase-3), and induced DNA fragmentation. Our data also demonstrated an increase in p21Waf1 expression, which correlated with increased p53 expression and MDM2 degradation following DATS treatment. Finally, histological assessment and enzyme assays showed that even the highest dose of DATS did not negatively impact hepatic function. Collectively, our results clearly demonstrated that DATS could be an effective therapeutic agent in preventing tumor progression and inducing apoptosis in human glioblastoma in vivo, without impairing hepatic function.
authors.affiliation: Department of Neurosciences (Neurology and Neuro-oncology) and MUSC Brain & Spine Tumor Program, Medical University of South Carolina, Charleston, SC 29425, USA.
authors.forename: Gerald C
authors.initials: GC
authors.lastname: Wallace
authors.forename: Catherine P
authors.initials: CP
authors.lastname: Haar
authors.forename: W Alex
authors.initials: WA
authors.lastname: Vandergrift
authors.forename: Pierre
authors.initials: P
authors.lastname: Giglio
authors.forename: Yaenette N
authors.initials: YN
authors.lastname: Dixon-Mah
authors.forename: Abhay K
authors.initials: AK
authors.lastname: Varma
authors.forename: Swapan K
authors.initials: SK
authors.lastname: Ray
authors.forename: Sunil J
authors.initials: SJ
authors.lastname: Patel
authors.forename: Naren L
authors.initials: NL
authors.lastname: Banik
authors.forename: Arabinda
authors.initials: A
authors.lastname: Das
mesh_terms: D000498:Allyl Compounds / Q000627:therapeutic use*; D000704:Analysis of Variance; D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D051017:Apoptosis Regulatory Proteins / Q000235:genetics / Q000378:metabolism; D001932:Brain Neoplasms / Q000188:drug therapy*; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D018450:Disease Progression; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D005909:Glioblastoma / Q000188:drug therapy*; D006655:Histone Deacetylases / Q000378:metabolism*; D006801:Humans; D020287:In Situ Nick-End Labeling; D008099:Liver / Q000473:pathology; D051379:Mice; D016513:Mice, SCID; D013440:Sulfides / Q000627:therapeutic use*; D023041:Xenograft Model Antitumor Assays
chemical_list: D000498:Allyl Compounds; D051017:Apoptosis Regulatory Proteins; D013440:Sulfides; C042577:diallyl trisulfide; D006655:Histone Deacetylases