Oncotarget

Research Papers:

Dual targeting of retinoid X receptor and histone deacetylase with DW22 as a novel antitumor approach

Lihui Wang _, Guoliang Chen, Kang Chen, Yong Ren, Huahuan Li, Xiaorui Jiang, Lina Jia, Shiyuan Fu, Yi Li, Xinwei Liu, Shuang Wang, Jingyu Yang and Chunfu Wu

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Oncotarget. 2015; 6:9740-9755. https://doi.org/10.18632/oncotarget.3149

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Abstract

Lihui Wang1,2, Guoliang Chen3, Kang Chen1,2, Yong Ren4, Huahuan Li1,2, Xiaorui Jiang1,2, Lina Jia1, Shiyuan Fu1,2, Yi Li1,2, Xinwei Liu1,2, Shuang Wang1,2, Jingyu Yang1,2, Chunfu Wu1,2

1Department of Pharmacology, Shenyang Pharmaceutical University, Shenyang, P.R. China

2Benxi Institute of Pharmaceutical Research, Shenyang Pharmaceutical University, Benxi, P.R. China

3Key Laboratory of Structure-Based Drugs Design & Discovery of Ministry of Education, Shenyang Pharmaceutical University, Shenyang, P.R. China

4Department of Pathology, Wuhan General Hospital of Guangzhou Command, People's Liberation Army, Wuhan, P.R. China

Correspondence to:

Jingyu Yang, e-mail: [email protected]

Chunfu Wu, e-mail: [email protected]

Keywords: Retinoid X receptor, Histone deacetylase, DW22, anti-tumor

Received: August 21, 2014     Accepted: January 17, 2015     Published: February 05, 2015

ABSTRACT

Retinoid X receptor (RXR) and Histone deacetylase (HDAC) are considered important targets for cancer therapy due to their crucial roles in genetic or epigenetic regulations of cancer development and progression. Here, we evaluated the potential of dual targeting of RXR and HDAC using DW22 as a novel therapeutic approach to cancer treatment. We found that the co-expression of RXR-α and HDAC1 was frequently appeared in lung cancer and breast cancer tissues and cell lines. RXR was activated by DW22 in RXRα and HDAC1 overexpressed A549 and MDA-MB-435 cell lines. Meanwhile, DW22 inhibited the activity of HDAC by decreasing its expression in A549 and MDA-MB-435 cell lines, but not in RXRα and HDAC1 deficient cell lines. Moreover, DW22 suppressed cell growth, induced cell differentiation, prompted cell apoptosis and arrested cell cycle in A549, MDA-MB-435 or HL60 cell lines. Treatment human umbilical vascular endothelial cells (HUVECs) with DW22 suppressed migration, invasion and tube formation through decreasing VEGF expression. The up-regulation of Ac-H3 and p21, and down-regulation of VEGF caused by DW22 was markedly attenuated by silencing of HDAC1. Furthermore, knockdown of RXRα by siRNA completely blocked DW22-induced cell differentiation, but partially attenuated DW22-caused inhibition of cell proliferation, induction of cell apoptosis, and suppression of cell migration, invasion and tube formation. Moreover, intravenous administration of DW22 significantly retarded tumor growth of A549 and MDA-MB-435 xenograft mice models, and induced no substantial weight loss and gross toxicity. In addition, DW22 also reduced cell proliferation, angiogenesis, and induced cell apoptosis in vivo. Collectively, our data demonstrates that dual targeting of RXR and HDAC using DW22 possesses pleiotropic antitumor activities both in vitro and in vivo, providing a novel therapeutic approach for cancer treatment.


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