SAHA-induced TRAIL-sensitisation of Multiple Myeloma cells is enhanced in 3D cell culture

ARHOMA, A., CHANTRY, A. D., HAYWOOD-SMALL, Sarah and CROSS, Neil (2017). SAHA-induced TRAIL-sensitisation of Multiple Myeloma cells is enhanced in 3D cell culture. Experimental cell research.

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Official URL: http://www.sciencedirect.com/science/article/pii/S...
Link to published version:: 10.1016/j.yexcr.2017.09.012

Abstract

Multiple Myeloma (MM) is currently incurable despite many novel therapies. Tumour Necrosis Factor-Related Apoptosis-Inducing Ligand (TRAIL) is a potential anti-tumour agent although effects as a single agent are limited. In this study, we investigated whether the Histone Deacetylase (HDAC) inhibitor SAHA can enhance TRAIL-induced apoptosis and target TRAIL resistance in both suspension culture, and 3D cell culture as a model of disseminated MM lesions that form in bone. The effects of SAHA and/or TRAIL in 6 Multiple Myeloma cell lines were assessed in both suspension cultures and in an Alginate-based 3D cell culture model. The effect of SAHA and/or TRAIL was assessed on apoptosis by assessment of nuclear morphology using Hoechst 33342/Propidium Iodide staining. Viable cell number was assessed by CellTiter-Glo luminescence assay, Caspase-8 and -9 activities were measured by Caspase-Glo™ assay kit. TRAIL-resistant cells were generated by culture of RPMI 8226 and NCI-H929 by acute exposure to TRAIL followed by selection of TRAIL-resistant cells. TRAIL significantly induced apoptosis in a dose-dependent manner in OPM-2, RPMI 8226, NCI-H929, U266, JJN-3 MM cell lines and ADC-1 plasma cell leukaemia cells. SAHA amplified TRAIL responses in all lines except OPM-2, and enhanced TRAIL responses were both via Caspase-8 and -9. SAHA treatment induced growth inhibition that further increased in the combination treatment with TRAIL in MM cells. The co-treatment of TRAIL and SAHA reduced viable cell numbers all cell lines. TRAIL responses were further potentiated by SAHA in 3D cell culture in NCI-H929, RPMI 8226 and U266 at lower TRAIL + SAHA doses than in suspension culture. However TRAIL responses in cells that had been selected for TRAIL resistance were not further enhanced by SAHA treatment. SAHA is a potent sensitizer of TRAIL responses in both TRAIL sensitive and resistant cell lines, in both suspension and 3D culture, however SAHA did not sensitise TRAIL-sensitive cell populations that had been selected for TRAIL-resistance from initially TRAIL-sensitive populations. SAHA may increase TRAIL sensitivity in insensitive cells, but not in cells that have specifically been selected for acquired TRAIL-resistance. [Abstract copyright: Copyright © 2017 Elsevier Inc. All rights reserved.]

Item Type: Article
Additional Information: ** From PubMed via Jisc Publications Router. ** History: ** received: 15-12-2016 ** revised: 05-09-2017 ** accepted: 06-09-2017
Uncontrolled Keywords: 3D cell culture, Apoptosis, Cell proliferation, Multiple Myeloma, SAHA, TRAIL
Research Institute, Centre or Group: Biomolecular Sciences Research Centre
Identification Number: 10.1016/j.yexcr.2017.09.012
SWORD Depositor: Jill Hazard
Depositing User: Jill Hazard
Date Deposited: 22 Sep 2017 13:24
Last Modified: 30 Sep 2017 17:36
URI: http://shura.shu.ac.uk/id/eprint/16826

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