title: Dual targeting of retinoid X receptor and histone deacetylase with DW22 as a novel antitumor approach.
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.
authors.affiliation: Department of Pharmacology, Shenyang Pharmaceutical University, Shenyang, P.R. China.|Benxi Institute of Pharmaceutical Research, Shenyang Pharmaceutical University, Benxi, P.R. China.
authors.forename: Lihui
authors.initials: L
authors.lastname: Wang
authors.affiliation: Key Laboratory of Structure-Based Drugs Design & Discovery of Ministry of Education, Shenyang Pharmaceutical University, Shenyang, P.R. China.
authors.forename: Guoliang
authors.initials: G
authors.lastname: Chen
authors.affiliation: Department of Pharmacology, Shenyang Pharmaceutical University, Shenyang, P.R. China.|Benxi Institute of Pharmaceutical Research, Shenyang Pharmaceutical University, Benxi, P.R. China.
authors.forename: Kang
authors.initials: K
authors.lastname: Chen
authors.affiliation: Department of Pathology, Wuhan General Hospital of Guangzhou Command, People's Liberation Army, Wuhan, P.R. China.
authors.forename: Yong
authors.initials: Y
authors.lastname: Ren
authors.affiliation: Department of Pharmacology, Shenyang Pharmaceutical University, Shenyang, P.R. China.|Benxi Institute of Pharmaceutical Research, Shenyang Pharmaceutical University, Benxi, P.R. China.
authors.forename: Huahuan
authors.initials: H
authors.lastname: Li
authors.affiliation: Department of Pharmacology, Shenyang Pharmaceutical University, Shenyang, P.R. China.|Benxi Institute of Pharmaceutical Research, Shenyang Pharmaceutical University, Benxi, P.R. China.
authors.forename: Xiaorui
authors.initials: X
authors.lastname: Jiang
authors.affiliation: Department of Pharmacology, Shenyang Pharmaceutical University, Shenyang, P.R. China.
authors.forename: Lina
authors.initials: L
authors.lastname: Jia
authors.affiliation: Department of Pharmacology, Shenyang Pharmaceutical University, Shenyang, P.R. China.|Benxi Institute of Pharmaceutical Research, Shenyang Pharmaceutical University, Benxi, P.R. China.
authors.forename: Shiyuan
authors.initials: S
authors.lastname: Fu
authors.affiliation: Department of Pharmacology, Shenyang Pharmaceutical University, Shenyang, P.R. China.|Benxi Institute of Pharmaceutical Research, Shenyang Pharmaceutical University, Benxi, P.R. China.
authors.forename: Yi
authors.initials: Y
authors.lastname: Li
authors.affiliation: Department of Pharmacology, Shenyang Pharmaceutical University, Shenyang, P.R. China.|Benxi Institute of Pharmaceutical Research, Shenyang Pharmaceutical University, Benxi, P.R. China.
authors.forename: Xinwei
authors.initials: X
authors.lastname: Liu
authors.affiliation: Department of Pharmacology, Shenyang Pharmaceutical University, Shenyang, P.R. China.|Benxi Institute of Pharmaceutical Research, Shenyang Pharmaceutical University, Benxi, P.R. China.
authors.forename: Shuang
authors.initials: S
authors.lastname: Wang
authors.affiliation: Department of Pharmacology, Shenyang Pharmaceutical University, Shenyang, P.R. China.|Benxi Institute of Pharmaceutical Research, Shenyang Pharmaceutical University, Benxi, P.R. China.
authors.forename: Jingyu
authors.initials: J
authors.lastname: Yang
authors.affiliation: Department of Pharmacology, Shenyang Pharmaceutical University, Shenyang, P.R. China.|Benxi Institute of Pharmaceutical Research, Shenyang Pharmaceutical University, Benxi, P.R. China.
authors.forename: Chunfu
authors.initials: C
authors.lastname: Wu
mesh_terms: D000368:Aged; D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D000077610:Bexarotene; D001943:Breast Neoplasms / Q000188:drug therapy / Q000378:metabolism; D002454:Cell Differentiation; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000378:metabolism; D004354:Drug Screening Assays, Antitumor; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D020868:Gene Silencing; D018922:HL-60 Cells; D056284:Histone Deacetylase 1 / Q000378:metabolism*; D006657:Histones / Q000378:metabolism; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D006877:Hydroxamic Acids / Q000627:therapeutic use*; D008175:Lung Neoplasms / Q000188:drug therapy / Q000378:metabolism; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D016513:Mice, SCID; D008875:Middle Aged; D009361:Neoplasm Invasiveness; D009368:Neoplasm Transplantation; D009389:Neovascularization, Pathologic; D034741:RNA, Small Interfering / Q000378:metabolism; D047490:Retinoid X Receptor alpha / Q000378:metabolism*; D013764:Tetrahydronaphthalenes / Q000627:therapeutic use*; D015854:Up-Regulation; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; C493956:CDKN1A protein, human; D050759:Cyclin-Dependent Kinase Inhibitor p21; D006657:Histones; D006877:Hydroxamic Acids; D034741:RNA, Small Interfering; D047490:Retinoid X Receptor alpha; D013764:Tetrahydronaphthalenes; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; C000606674:bexarotene hydroxamic acid; D000077610:Bexarotene; C110550:HDAC1 protein, human; D056284:Histone Deacetylase 1
keywords: DW22; anti-tumor; histone deacetylase; retinoid X receptor