Histone deacetylase inhibitor trichostatin A sensitises cisplatin-resistant ovarian cancer cells to oncolytic adenovirus

Hulin-Curtis, Sarah L ORCID: 0000-0003-0889-964X, Davies, James A, Jones, Rachel, Hudson, Emma, Hanna, Louise, Chester, John D and Parker, Alan L (2018) Histone deacetylase inhibitor trichostatin A sensitises cisplatin-resistant ovarian cancer cells to oncolytic adenovirus. Oncotarget, 9 (41). pp. 26328-26341. doi:10.18632/oncotarget.25242

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Text 14144 Hulin-Curtis, Davies, Jones, Hudson, Hanna, Chester, Parker (2018) Histone deacetylase inhibitor trichostatin A sensities cisplatin-resistant ovarian cancer cells to oncolytic adenovirus.pdf - Published Version Available under License Creative Commons Attribution 3.0. Download (2MB) | Preview

Abstract

Ovarian cancer is often termed a silent killer due to the late onset of symptoms. Whilst patients initially respond to chemotherapy, they rapidly develop chemo-resistance. Oncolytic adenoviruses (OAds) are promising anti-cancer agents engineered to “hijack” the unique molecular machinery of cancer cells enabling tumour-selective viral replication. This allows spread to adjacent cells and amplification of oncolysis within the tumour. OAds represent an excellent opportunity for ovarian cancer therapy via intra-peritoneal delivery, however the efficacy of OAds thus far is limited. Here, we evaluate chromatin (histone) modification in chemo-resistant cells and its relationship to Ad efficacy (wild-type or oncolytic Ad). In contrast to cisplatin-sensitive A2780 cells that show an efficient reduction of cell viability by Ad in the presence of cisplatin, cisplatin-resistant A2780/cp70 cells show diminishing Ad-mediated reduction of cell viability with escalating doses of cisplatin. Histone deacetylase (HDAC)-2 and to a lesser extent HDAC1 were up-regulated in cisplatin-resistant but not cisplatin-sensitive cells. Cisplatin-resistant cells treated with a pan-HDAC inhibitor trichostatin A (TsA) significantly enhanced Ad-mediated reduction of cell viability in the presence of cisplatin. Cells treated with TsA alone did not reduce cell viability suggesting these findings are Ad-dependent. Thus, we identify HDAC inhibition as a potential means to sensitise cisplatin-resistant ovarian cancer cells to virotherapies, an observation that may offer improved outcomes for patients with late stage, chemotherapy-resistant ovarian cancer.

Item Type:	Article
Article Type:	Article
Uncontrolled Keywords:	Histone deacetylase inhibitor; Oncolytic adenovirus; Cisplatin-resistance; Ovarian cancer
Subjects:	R Medicine > R Medicine (General)
Divisions:	Schools and Research Institutes > School of Education and Science
Research Priority Areas:	Health, Life Sciences, Sport and Wellbeing
Depositing User:	Sarah Curtis
Date Deposited:	17 Jun 2024 09:04
Last Modified:	17 Jun 2024 09:15
URI:	https://eprints.glos.ac.uk/id/eprint/14144

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