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GM101 in Combination with Histone Deacetylase Inhibitor Enhances Anti-Tumor Effects in Desmoplastic Microenvironment.
Chang, Han-Gyu; Choi, Yong-Hyeon; Hong, JinWoo; Choi, Joung-Woo; Yoon, A-Rum; Yun, Chae-Ok.
Afiliação
  • Chang HG; Department of Bioengineering, College of Engineering, Hanyang University, 222 Wangsimni-ro, Seongdong-gu, Seoul 04763, Korea.
  • Choi YH; GeneMedicine CO., Ltd., 222 Wangsimni-ro, Seongdong-gu, Seoul 04763, Korea.
  • Hong J; GeneMedicine CO., Ltd., 222 Wangsimni-ro, Seongdong-gu, Seoul 04763, Korea.
  • Choi JW; Department of Bioengineering, College of Engineering, Hanyang University, 222 Wangsimni-ro, Seongdong-gu, Seoul 04763, Korea.
  • Yoon AR; Department of Bioengineering, College of Engineering, Hanyang University, 222 Wangsimni-ro, Seongdong-gu, Seoul 04763, Korea.
  • Yun CO; Institute of Nano Science and Technology (INST), Hanyang University, 222 Wangsimni-ro, Seongdong-gu, Seoul 04763, Korea.
Cells ; 10(11)2021 10 20.
Article em En | MEDLINE | ID: mdl-34831034
ABSTRACT
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.
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Inibidores de Histona Desacetilases / Microambiente Tumoral / Antineoplásicos Tipo de estudo: Prognostic_studies Limite: Animals / Humans / Male Idioma: En Revista: Cells Ano de publicação: 2021 Tipo de documento: Article

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Inibidores de Histona Desacetilases / Microambiente Tumoral / Antineoplásicos Tipo de estudo: Prognostic_studies Limite: Animals / Humans / Male Idioma: En Revista: Cells Ano de publicação: 2021 Tipo de documento: Article