PMID- 30209569 OWN - NLM STAT- MEDLINE DCOM- 20190828 LR - 20200424 IS - 1432-0843 (Electronic) IS - 0344-5704 (Linking) VI - 82 IP - 6 DP - 2018 Dec TI - Single agent efficacy of the HDAC inhibitor DATS in preclinical models of glioblastoma. PG - 945-952 LID - 10.1007/s00280-018-3684-7 [doi] AB - PURPOSE/INTRODUCTION: Glioblastoma (GB) remains incurable despite aggressive chemotherapy, radiotherapy, and surgical interventions; immunotherapies remain experimental in clinical practice. Relevant preclinical models that can accurately predict tumor response to therapy are equally challenging. This study aimed to validate the effect of the naturally occurring agent diallyl trisulfide (DATS) in human GB in relevant pre-clinical models. METHODS: Ex vivo slice culture, in vivo cell line derived orthotopic xenograft and patient-derived orthotopic xenograft (PDX) animal models of GB were utilized to assess efficacy of treatment with DATS. RESULTS: Our results showed 72-h treatments of 25 microM DATS induced cell death in ex vivo human GB slice culture. We treated U87MG orthotopic xenograft models (U87MGOX) and patient-derived orthotopic xenograft models (PDX) with daily intraperitoneal injections of DATS for 14 days. Magnetic resonance (MR) imaging of mice treated with DATS (10 mg/kg) demonstrated reduced tumor size at 5 weeks when compared with saline-treated U87MGOX and PDX controls. Hematoxylin (H&E) staining demonstrated dose-dependent reduction in gross tumor volume with decreased proliferation and decreased angiogenesis. Western blotting showed that DATS was associated with increases in histone acetylation (Ac-Histone H3/H4) and activated caspase-3 in this novel preclinical model. Histological assessment and enzyme assays showed that even the highest dose of DATS did not negatively impact hepatic function. CONCLUSIONS: DATS may be an effective and well-tolerated therapeutic agent in preventing tumor progression and inducing apoptosis in human GB. FAU - Das, Arabinda AU - Das A AUID- ORCID: 0000-0002-0086-4760 AD - Divisions of Neuro-oncology, Department of Neurosurgery and MUSC Brain and Spine Tumor Program CSB 310, Medical University of South Carolina, Charleston, SC, 29425, USA. dasa@musc.edu. FAU - Henderson, Fraser Jr AU - Henderson F Jr AD - Divisions of Neuro-oncology, Department of Neurosurgery and MUSC Brain and Spine Tumor Program CSB 310, Medical University of South Carolina, Charleston, SC, 29425, USA. FAU - Lowe, Stephen AU - Lowe S AD - Divisions of Neuro-oncology, Department of Neurosurgery and MUSC Brain and Spine Tumor Program CSB 310, Medical University of South Carolina, Charleston, SC, 29425, USA. FAU - Wallace, Gerald C 4th AU - Wallace GC 4th AD - Divisions of Neuro-oncology, Department of Neurosurgery and MUSC Brain and Spine Tumor Program CSB 310, Medical University of South Carolina, Charleston, SC, 29425, USA. FAU - Vandergrift, William A 3rd AU - Vandergrift WA 3rd AD - Divisions of Neuro-oncology, Department of Neurosurgery and MUSC Brain and Spine Tumor Program CSB 310, Medical University of South Carolina, Charleston, SC, 29425, USA. FAU - Lindhorst, Scott M AU - Lindhorst SM AD - Divisions of Neuro-oncology, Department of Neurosurgery and MUSC Brain and Spine Tumor Program CSB 310, Medical University of South Carolina, Charleston, SC, 29425, USA. FAU - Varma, Abhay K AU - Varma AK AD - Divisions of Neuro-oncology, Department of Neurosurgery and MUSC Brain and Spine Tumor Program CSB 310, Medical University of South Carolina, Charleston, SC, 29425, USA. FAU - Infinger, Libby K AU - Infinger LK AD - Divisions of Neuro-oncology, Department of Neurosurgery and MUSC Brain and Spine Tumor Program CSB 310, Medical University of South Carolina, Charleston, SC, 29425, USA. FAU - Giglio, Pierre AU - Giglio P AD - Department of Neurological Surgery, Ohio State University Wexner Medical College, Columbus, OH, USA. FAU - Banik, Narendra L AU - Banik NL AD - Divisions of Neuro-oncology, Department of Neurosurgery and MUSC Brain and Spine Tumor Program CSB 310, Medical University of South Carolina, Charleston, SC, 29425, USA. AD - Research, Ralph H. Johnson Veterans Administration Medical Center, Charleston, South Carolina, United States. FAU - Patel, Sunil J AU - Patel SJ AD - Divisions of Neuro-oncology, Department of Neurosurgery and MUSC Brain and Spine Tumor Program CSB 310, Medical University of South Carolina, Charleston, SC, 29425, USA. FAU - Cachia, David AU - Cachia D AD - Divisions of Neuro-oncology, Department of Neurosurgery and MUSC Brain and Spine Tumor Program CSB 310, Medical University of South Carolina, Charleston, SC, 29425, USA. LA - eng GR - C06 RR015455/RR/NCRR NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, Non-U.S. Gov't DEP - 20180912 PL - Germany TA - Cancer Chemother Pharmacol JT - Cancer chemotherapy and pharmacology JID - 7806519 RN - 0 (Allyl Compounds) RN - 0 (Histone Deacetylase Inhibitors) RN - 0 (Sulfides) RN - 0ZO1U5A3XX (diallyl trisulfide) RN - EC 3.5.1.98 (Histone Deacetylases) SB - IM MH - Allyl Compounds/administration & dosage/*therapeutic use MH - Animals MH - Apoptosis/drug effects MH - Astrocytes/drug effects/pathology MH - Cell Line, Tumor MH - Dose-Response Relationship, Drug MH - Glioblastoma/*drug therapy/enzymology/pathology MH - Histone Deacetylase Inhibitors/administration & dosage/*therapeutic use MH - Histone Deacetylases/*metabolism MH - Humans MH - Male MH - Mice, SCID MH - Neurons/drug effects/pathology MH - Sulfides/administration & dosage/*therapeutic use MH - Xenograft Model Antitumor Assays OTO - NOTNLM OT - DATS OT - Diallyl trisulfide OT - GB OT - Glioblastoma OT - Histone deacetylase inhibitor OT - PDX: patient-derived orthotopic xenograft EDAT- 2018/09/14 06:00 MHDA- 2019/08/29 06:00 CRDT- 2018/09/14 06:00 PHST- 2018/07/14 00:00 [received] PHST- 2018/09/06 00:00 [accepted] PHST- 2018/09/14 06:00 [pubmed] PHST- 2019/08/29 06:00 [medline] PHST- 2018/09/14 06:00 [entrez] AID - 10.1007/s00280-018-3684-7 [pii] AID - 10.1007/s00280-018-3684-7 [doi] PST - ppublish SO - Cancer Chemother Pharmacol. 2018 Dec;82(6):945-952. doi: 10.1007/s00280-018-3684-7. Epub 2018 Sep 12.