GM101 in Combination with Histone Deacetylase Inhibitor Enhances Anti-Tumor Effects in Desmoplastic Microenvironment

Oncolytic adenoviruses (oAds) have been evaluated in numerous clinical trials due to their promising attributes as cancer therapeutics. However, the therapeutic efficacy of oAds was limited due to variable coxsackie and adenovirus receptor (CAR) expression levels and the dense extracellular matrix (...

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Autores principales:	Han-Gyu Chang, Yong-Hyeon Choi, JinWoo Hong, Joung-Woo Choi, A-Rum Yoon, Chae-Ok Yun
Formato:	article
Lenguaje:	EN
Publicado:	MDPI AG 2021
Materias:	GM101 histone deacetylase inhibitor MS-275 SBHA CAR receptor dynamin Biology (General) QH301-705.5
Acceso en línea:	https://doaj.org/article/7f74688d253c485e9353a7d625c1d61d
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spelling	oai:doaj.org-article:7f74688d253c485e9353a7d625c1d61d2021-11-25T17:07:24ZGM101 in Combination with Histone Deacetylase Inhibitor Enhances Anti-Tumor Effects in Desmoplastic Microenvironment10.3390/cells101128112073-4409https://doaj.org/article/7f74688d253c485e9353a7d625c1d61d2021-10-01T00:00:00Zhttps://www.mdpi.com/2073-4409/10/11/2811https://doaj.org/toc/2073-4409Oncolytic adenoviruses (oAds) have been evaluated in numerous clinical trials due to their promising attributes as cancer therapeutics. However, the therapeutic efficacy of oAds was limited due to variable coxsackie and adenovirus receptor (CAR) expression levels and the dense extracellular matrix (ECM) of heterogenic clinical tumors. To overcome these limitations, our present report investigated the therapeutic efficacy of combining GM101, an oAd with excellent tumor ECM degrading properties, and histone deacetylase inhibitor (HDACi). Four different HDACi (suberohydroxamic acid (SBHA), MS-275, trichostatin A (TSA), and valproic acid) candidates in combination with replication-incompetent and GFP-expressing Ad (dAd/GFP) revealed that SBHA and MS-275 exerted more potent enhancement in Ad transduction efficacy than TSA or valproic acid. Further characterization revealed that SBHA and MS-275 effectively upregulated CAR expression in cancer cells, improved the binding of Ad with cancer cell membranes, and led to dynamin 2- and clathrin-mediated endocytosis of Ad. The combination of GM101 with HDACi induced superior cancer cell killing effects compared to any of the monotherapies, without any additional cytotoxicity in normal cell lines. Further, GM101+SBHA and GM101+MS-275 induced more potent antitumor efficacy than any monotherapy in U343 xenograft tumor model. Potent antitumor efficacy was achieved via the combination of GM101 with HDACi, inducing necrotic and apoptotic cancer cell death, inhibiting cancer cell proliferation, degrading ECM in tumor tissue, and thus exerting the highest level of virus dispersion and accumulation. Collectively, these data demonstrate that the combination of GM101 and HDACi can enhance intratumoral dispersion and accumulation of oAd through multifaced mechanisms, making it a promising strategy to address the challenges toward successful clinical development of oAd.Han-Gyu ChangYong-Hyeon ChoiJinWoo HongJoung-Woo ChoiA-Rum YoonChae-Ok YunMDPI AGarticleGM101histone deacetylase inhibitorMS-275SBHACAR receptordynaminBiology (General)QH301-705.5ENCells, Vol 10, Iss 2811, p 2811 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	GM101 histone deacetylase inhibitor MS-275 SBHA CAR receptor dynamin Biology (General) QH301-705.5
spellingShingle	GM101 histone deacetylase inhibitor MS-275 SBHA CAR receptor dynamin Biology (General) QH301-705.5 Han-Gyu Chang Yong-Hyeon Choi JinWoo Hong Joung-Woo Choi A-Rum Yoon Chae-Ok Yun GM101 in Combination with Histone Deacetylase Inhibitor Enhances Anti-Tumor Effects in Desmoplastic Microenvironment
description	Oncolytic adenoviruses (oAds) have been evaluated in numerous clinical trials due to their promising attributes as cancer therapeutics. However, the therapeutic efficacy of oAds was limited due to variable coxsackie and adenovirus receptor (CAR) expression levels and the dense extracellular matrix (ECM) of heterogenic clinical tumors. To overcome these limitations, our present report investigated the therapeutic efficacy of combining GM101, an oAd with excellent tumor ECM degrading properties, and histone deacetylase inhibitor (HDACi). Four different HDACi (suberohydroxamic acid (SBHA), MS-275, trichostatin A (TSA), and valproic acid) candidates in combination with replication-incompetent and GFP-expressing Ad (dAd/GFP) revealed that SBHA and MS-275 exerted more potent enhancement in Ad transduction efficacy than TSA or valproic acid. Further characterization revealed that SBHA and MS-275 effectively upregulated CAR expression in cancer cells, improved the binding of Ad with cancer cell membranes, and led to dynamin 2- and clathrin-mediated endocytosis of Ad. The combination of GM101 with HDACi induced superior cancer cell killing effects compared to any of the monotherapies, without any additional cytotoxicity in normal cell lines. Further, GM101+SBHA and GM101+MS-275 induced more potent antitumor efficacy than any monotherapy in U343 xenograft tumor model. Potent antitumor efficacy was achieved via the combination of GM101 with HDACi, inducing necrotic and apoptotic cancer cell death, inhibiting cancer cell proliferation, degrading ECM in tumor tissue, and thus exerting the highest level of virus dispersion and accumulation. Collectively, these data demonstrate that the combination of GM101 and HDACi can enhance intratumoral dispersion and accumulation of oAd through multifaced mechanisms, making it a promising strategy to address the challenges toward successful clinical development of oAd.
format	article
author	Han-Gyu Chang Yong-Hyeon Choi JinWoo Hong Joung-Woo Choi A-Rum Yoon Chae-Ok Yun
author_facet	Han-Gyu Chang Yong-Hyeon Choi JinWoo Hong Joung-Woo Choi A-Rum Yoon Chae-Ok Yun
author_sort	Han-Gyu Chang
title	GM101 in Combination with Histone Deacetylase Inhibitor Enhances Anti-Tumor Effects in Desmoplastic Microenvironment
title_short	GM101 in Combination with Histone Deacetylase Inhibitor Enhances Anti-Tumor Effects in Desmoplastic Microenvironment
title_full	GM101 in Combination with Histone Deacetylase Inhibitor Enhances Anti-Tumor Effects in Desmoplastic Microenvironment
title_fullStr	GM101 in Combination with Histone Deacetylase Inhibitor Enhances Anti-Tumor Effects in Desmoplastic Microenvironment
title_full_unstemmed	GM101 in Combination with Histone Deacetylase Inhibitor Enhances Anti-Tumor Effects in Desmoplastic Microenvironment
title_sort	gm101 in combination with histone deacetylase inhibitor enhances anti-tumor effects in desmoplastic microenvironment
publisher	MDPI AG
publishDate	2021
url	https://doaj.org/article/7f74688d253c485e9353a7d625c1d61d
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GM101 in Combination with Histone Deacetylase Inhibitor Enhances Anti-Tumor Effects in Desmoplastic Microenvironment

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