Influence of a novel histone deacetylase inhibitor panobinostat (LBH589) on the growth of ovarian cancer

• Published in: Journal of ovarian research Vol. 9; no. 1; p. 58
• Main Authors: Garrett, Leslie A, Growdon, Whitfield B, Rueda, Bo R, Foster, Rosemary
• Format: Journal Article
• Language: English
• Published: England BioMed Central Ltd 15.09.2016; BioMed Central
• Subjects: Analysis; Animals; Antineoplastic Agents - pharmacology; Biomarkers; Cancer; Care and treatment; Cell Line, Tumor; Cell Proliferation - drug effects; Cell Survival - drug effects; Chemotherapy; Disease Models, Animal; Drug Evaluation, Preclinical; Female; Health aspects; Histone Deacetylase Inhibitors - pharmacology; Histones; Humans; Hydroxamic Acids - pharmacology; Indoles - pharmacology; Mice; Mice, Inbred NOD; Mice, SCID; Neoplasm Grading; Ovarian cancer; Ovarian Neoplasms - drug therapy; Ovarian Neoplasms - metabolism; Ovarian Neoplasms - pathology; Risk factors; Tumor Burden - drug effects; Vitrectomy; Xenograft Model Antitumor Assays; Patient derived xenograft model; Histone deacetylase inhibitor; Conventional chemotherapy; Ovarian cancer
• ISSN: 1757-2215; 1757-2215
• DOI: 10.1186/s13048-016-0267-2

Pre-clinical studies have demonstrated that natural and synthetic histone deacetylase (HDAC) inhibitors can impede the in vitro and in vivo growth of cell lines from a variety of gynecologic and other malignancies. We investigated the anti-tumor activity of panobinostat (LBH589) both in vitro and in vivo as either a single agent or in combination with conventional cytotoxic chemotherapy using patient-derived xenograft (PDX) models of primary serous ovarian tumors. The ovarian cancer cell lines OVCAR8, SKOV3 and their paclitaxel-resistant derivatives OVCAR8-TR and SKOV3-TR were treated with increasing doses of LBH589. The effect of LBH589 on cell viability was assessed using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. Serially transplanted primary human high-grade serous ovarian adenocarcinoma tissue was utilized to generate xenografts in 6-week old female NOD/SCID mice. The mice were then randomized into one of 4 treatment groups: (1) vehicle control; (2) paclitaxel and carboplatin (P/C); (3) LBH589; or (4) P/C + LBH589. Mice were treated for 21 days and tumor volumes and mouse weights were obtained every 3 days. These experiments were performed in triplicate with three different patient derived tumors. Wilcoxan rank-sum testing was utilized to assess tumor volume differences. In vitro treatment with LBH589 significantly reduced the viability of both taxol-sensitive and taxol-resistant ovarian cancer cell lines (p < 0.01). In vivo treatment with LBH589 alone appeared tumorstatic and reduced tumor growth when compared to vehicle treatment (p < 0.007) after 21 days. This single agent activity was confirmed in two additional experiments with other PDX tumors (p < 0.03, p < 0.05). A potential additive effect of LBH589 and P/C, manifested as enhanced tumor regression with the addition of LBH589 compared to vehicle (p < 0.02), in one of the three analyzed serous PDX models. Our findings suggest that pan-HDAC inhibition with panobinostat precludes the growth of ovarian cancer cell lines in vitro and PDXs in vivo. Added benefit of LBH589 to standard P/C therapy was observed in one of three PDX models suggesting improved response in a subset of serous ovarian cancers.