Single agent efficacy of the HDAC inhibitor DATS in preclinical models of glioblastoma

• Published in: Cancer chemotherapy and pharmacology Vol. 82; no. 6; pp. 945 - 952
• Main Authors: Das, Arabinda, Henderson, Fraser, Lowe, Stephen, Wallace, Gerald C., Vandergrift, William A., Lindhorst, Scott M., Varma, Abhay K., Infinger, Libby K., Giglio, Pierre, Banik, Narendra L., Patel, Sunil J., Cachia, David
• Format: Journal Article
• Language: English
• Published: Berlin/Heidelberg Springer Berlin Heidelberg 01.12.2018; Springer Nature B.V
• Subjects: Acetylation; Allyl Compounds - administration & dosage; Allyl Compounds - therapeutic use; Angiogenesis; Animal models; Animals; Apoptosis; Apoptosis - drug effects; Astrocytes - drug effects; Astrocytes - pathology; Brain cancer; Cancer Research; Cancer therapies; Caspase; Caspase-3; Cell culture; Cell death; Cell Line, Tumor; Chemical compounds; Chemotherapy; Diallyl trisulfide; Dose-Response Relationship, Drug; Glioblastoma; Glioblastoma - drug therapy; Glioblastoma - enzymology; Glioblastoma - pathology; Histone deacetylase; Histone Deacetylase Inhibitors - administration & dosage; Histone Deacetylase Inhibitors - therapeutic use; Histone Deacetylases - metabolism; Histone H3; Humans; Immunotherapy; In vivo methods and tests; Inhibitor drugs; Magnetic resonance imaging; Male; Medicine; Medicine & Public Health; Mice, SCID; Neurons - drug effects; Neurons - pathology; Oncology; Original Article; Patients; Pharmacology; Pharmacology/Toxicology; Radiation therapy; Sulfides - administration & dosage; Sulfides - therapeutic use; Surgery; Tumors; Western blotting; Xenograft Model Antitumor Assays; Xenografts; Xenotransplantation; Histone deacetylase inhibitor; PDX: patient-derived orthotopic xenograft; DATS; GB; Diallyl trisulfide; Glioblastoma
• ISSN: 0344-5704; 1432-0843
• DOI: 10.1007/s00280-018-3684-7

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 µM 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.