A novel combination of oridonin and valproic acid in enhancement of apoptosis induction of HL-60 leukemia cells

Shi,Meiyan; Ren,Xia; Wang,Xidi; Wang,Hengxiao; Liu,Guoqiang; Yuan,Xiaofen; Zheng,Shubo; Yu,Linchang; Pan,Sufei; Song,Guanhua; Guo,Qiang; Li,Lianlian; Zhang,Xiaoyu; Zhang,Zhiyong; Ding,Huifang; Jiang,Guosheng

doi:10.3892/ijo.2015.3294

A novel combination of oridonin and valproic acid in enhancement of apoptosis induction of HL-60 leukemia cells

Authors:
- Meiyan Shi
- Xia Ren
- Xidi Wang
- Hengxiao Wang
- Guoqiang Liu
- Xiaofen Yuan
- Shubo Zheng
- Linchang Yu
- Sufei Pan
- Guanhua Song
- Qiang Guo
- Lianlian Li
- Xiaoyu Zhang
- Zhiyong Zhang
- Huifang Ding
- Guosheng Jiang
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Affiliations: 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, Laboratory Department, People's Hospital of Zhangqiu City, Zhangqiu, Shandong, P.R. China, Department of Hematology, Shengli Oilfield Central Hospital, Dongying, Shandong, P.R. China, General Surgery Department, People's Hospital of Wenshang County, Wenshang, Shandong, P.R. China
Published online on: December 15, 2015 https://doi.org/10.3892/ijo.2015.3294
Pages: 734-746

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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.

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