title: A novel combination of oridonin and valproic acid in enhancement of apoptosis induction of HL-60 leukemia cells.
abstract: Oridonin, obtained from the traditional Chinese herbal medicine rabdosia rubescens, exerts potent antitumor activities in cancer cells. Valproic acid (VPA), as a potent histone deacetylase inhibitor (HDACI), also plays an important role in inhibition of proliferation of tumor cells. However, there are no reports so far on the cooperation between oridonin and VPA for anti-leukemic effect. Therefore, in the present study, we undertook experiments to determine whether lower concentration of oridonin in conjunction with lower concentration of VPA would produce even more encouraging synergistic effect than each of them alone, and to clarify its molecular mechanism. The results demonstrated that the lower concentration of oridonin in combination with lower concentration of VPA synergistically inhibited the proliferation of HL-60 cells, and induced obvious caspase-dependent apoptosis through activation of the intrinsic apoptosis pathway, which is involved in the downregulation of Bcl-2/Bax ratio, release of cytochrome c to cytosol and caspase-9 activation, as well as through the extrinsic apoptosis pathway mediated by Fas/FasL and caspase-8 activation. In addition, MAPK signaling pathway was also involved in apoptosis induced by oridonin plus VPA. Furthermore, the combination treatment in vivo remarkably reduced the xenograft tumor size and triggered tumor cell apoptosis. Taken together, the novel combination of oridonin plus VPA exerted synergistic anti-proliferative and apoptosis-inducing effects on human myeloid leukemia cells, and may serve as a potential promising anti-leukemia strategy.
authors.affiliation: Key Laboratory for Rare and Uncommon Diseases of Shandong Province, Key Laboratory for Tumor Immunology and Chinese Medicine Immunology of Shandong Province, Institute of Basic Medicine, Shandong Academy of Medical Sciences, Jinan University, Jinan, Shandong, P.R. China.
authors.forename: Meiyan
authors.initials: M
authors.lastname: Shi
authors.affiliation: Key Laboratory for Rare and Uncommon Diseases of Shandong Province, Key Laboratory for Tumor Immunology and Chinese Medicine Immunology of Shandong Province, Institute of Basic Medicine, Shandong Academy of Medical Sciences, Jinan University, Jinan, Shandong, P.R. China.
authors.forename: Xia
authors.initials: X
authors.lastname: Ren
authors.affiliation: Laboratory Department, People's Hospital of Zhangqiu City, Zhangqiu, Shandong, P.R. China.
authors.forename: Xidi
authors.initials: X
authors.lastname: Wang
authors.affiliation: Key Laboratory for Rare and Uncommon Diseases of Shandong Province, Key Laboratory for Tumor Immunology and Chinese Medicine Immunology of Shandong Province, Institute of Basic Medicine, Shandong Academy of Medical Sciences, Jinan University, Jinan, Shandong, P.R. China.
authors.forename: Hengxiao
authors.initials: H
authors.lastname: Wang
authors.affiliation: Department of Hematology, Shengli Oilfield Central Hospital, Dongying, Shandong, P.R. China.
authors.forename: Guoqiang
authors.initials: G
authors.lastname: Liu
authors.affiliation: Key Laboratory for Rare and Uncommon Diseases of Shandong Province, Key Laboratory for Tumor Immunology and Chinese Medicine Immunology of Shandong Province, Institute of Basic Medicine, Shandong Academy of Medical Sciences, Jinan University, Jinan, Shandong, P.R. China.
authors.forename: Xiaofen
authors.initials: X
authors.lastname: Yuan
authors.affiliation: General Surgery Department, People's Hospital of Wenshang County, Wenshang, Shandong, P.R. China.
authors.forename: Shubo
authors.initials: S
authors.lastname: Zheng
authors.affiliation: Key Laboratory for Rare and Uncommon Diseases of Shandong Province, Key Laboratory for Tumor Immunology and Chinese Medicine Immunology of Shandong Province, Institute of Basic Medicine, Shandong Academy of Medical Sciences, Jinan University, Jinan, Shandong, P.R. China.
authors.forename: Linchang
authors.initials: L
authors.lastname: Yu
authors.affiliation: Department of Hematology, Shengli Oilfield Central Hospital, Dongying, Shandong, P.R. China.
authors.forename: Sufei
authors.initials: S
authors.lastname: Pan
authors.affiliation: Key Laboratory for Rare and Uncommon Diseases of Shandong Province, Key Laboratory for Tumor Immunology and Chinese Medicine Immunology of Shandong Province, Institute of Basic Medicine, Shandong Academy of Medical Sciences, Jinan University, Jinan, Shandong, P.R. China.
authors.forename: Guanhua
authors.initials: G
authors.lastname: Song
authors.affiliation: Key Laboratory for Rare and Uncommon Diseases of Shandong Province, Key Laboratory for Tumor Immunology and Chinese Medicine Immunology of Shandong Province, Institute of Basic Medicine, Shandong Academy of Medical Sciences, Jinan University, Jinan, Shandong, P.R. China.
authors.forename: Qiang
authors.initials: Q
authors.lastname: Guo
authors.affiliation: Key Laboratory for Rare and Uncommon Diseases of Shandong Province, Key Laboratory for Tumor Immunology and Chinese Medicine Immunology of Shandong Province, Institute of Basic Medicine, Shandong Academy of Medical Sciences, Jinan University, Jinan, Shandong, P.R. China.
authors.forename: Lianlian
authors.initials: L
authors.lastname: Li
authors.affiliation: Key Laboratory for Rare and Uncommon Diseases of Shandong Province, Key Laboratory for Tumor Immunology and Chinese Medicine Immunology of Shandong Province, Institute of Basic Medicine, Shandong Academy of Medical Sciences, Jinan University, Jinan, Shandong, P.R. China.
authors.forename: Xiaoyu
authors.initials: X
authors.lastname: Zhang
authors.affiliation: Key Laboratory for Rare and Uncommon Diseases of Shandong Province, Key Laboratory for Tumor Immunology and Chinese Medicine Immunology of Shandong Province, Institute of Basic Medicine, Shandong Academy of Medical Sciences, Jinan University, Jinan, Shandong, P.R. China.
authors.forename: Zhiyong
authors.initials: Z
authors.lastname: Zhang
authors.affiliation: Department of Hematology, Shengli Oilfield Central Hospital, Dongying, Shandong, P.R. China.
authors.forename: Huifang
authors.initials: H
authors.lastname: Ding
authors.affiliation: Key Laboratory for Rare and Uncommon Diseases of Shandong Province, Key Laboratory for Tumor Immunology and Chinese Medicine Immunology of Shandong Province, Institute of Basic Medicine, Shandong Academy of Medical Sciences, Jinan University, Jinan, Shandong, P.R. China.
authors.forename: Guosheng
authors.initials: G
authors.lastname: Jiang
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D053181:Caspase 8 / Q000378:metabolism; D053453:Caspase 9 / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D045304:Cytochromes c / Q000378:metabolism; D045786:Diterpenes, Kaurane / Q000494:pharmacology*; D004359:Drug Therapy, Combination / Q000379:methods; D053222:Fas Ligand Protein / Q000378:metabolism; D018922:HL-60 Cells; D006801:Humans; D007938:Leukemia / Q000188:drug therapy* / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D014635:Valproic Acid / Q000494:pharmacology*; D051028:bcl-2-Associated X Protein / Q000378:metabolism
chemical_list: D045786:Diterpenes, Kaurane; C505661:FASLG protein, human; D053222:Fas Ligand Protein; D019253:Proto-Oncogene Proteins c-bcl-2; D051028:bcl-2-Associated X Protein; C011959:oridonin; D014635:Valproic Acid; D045304:Cytochromes c; D053181:Caspase 8; D053453:Caspase 9