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Original Article Hispidulin Induces Mitochondrial Apoptosis in Acute Myeloid Leukemia Cells by Targeting Extracellular Matrix Metalloproteinase Inducer

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Original Article Hispidulin Induces Mitochondrial Apoptosis in Acute Myeloid Leukemia Cells by Targeting Extracellular Matrix Metalloproteinase Inducer Am J Transl Res 2016;8(2):1115-1132 www.ajtr.org /ISSN:1943-8141/AJTR0014691 Original Article Hispidulin induces mitochondrial apoptosis in acute myeloid leukemia cells by targeting extracellular matrix metalloproteinase inducer Hui Gao1*, Yongji Liu2*, Kan Li3, Tianhui Wu4, Jianjun Peng5, Fanbo Jing6 1Qingdao University Medical College, Qingdao, Shandong, 266071, China; 2Qingdao Hiser Medical Center, Qingdao, Shandong 266000, China; 3Shandong Provincial Hospital Affiliated to Shandong University, Shandong 250021, China; 4Qingdao 5th People’s Hospital, Qingdao, Shandong 266000, China; 5College of Life Sciences, Chongqing Normal University, Chongqing 401331, China; 6The Affiliated Hospital of Qingdao University, Qingdao, Shandong 266003, China. *Equal contributors. Received August 18, 2015; Accepted January 12, 2016; Epub February 15, 2016; Published February 29, 2016 Abstract: Acute myeloid leukemia (AML) represents a heterogeneous group of hematological neoplasms with marked heterogeneity in response to both standard therapy and survival. Hispidulin, a flavonoid compound that is anactive ingredient in the traditional Chinese medicinal herb Salvia plebeia R. Br, has recently been reported to have anantitumor effect against solid tumors in vitro and in vivo. The aim of the present study was to investigate the effects of hispidulin on the human leukemia cell line in vitro and the underlying mechanisms of its actions on these cells. Our results showed that hispidulin inhibits AML cell proliferation in a dose- and time-dependent man- ner, and induces cell apoptosis throughan intrinsic mitochondrial pathway. Our results also revealed that hispidulin treatment significantly inhibits extracellular matrix metalloproteinase inducer (EMMPRIN) expression in both tested AML cell lines in a dose-dependent manner, and that the overexpression of EMMPRIN protein markedly attenuates hispidulin-induced cell apoptosis. Furthermore, our results strongly indicated that the modulating effect of hispidu- lin on EMMPRIN is correlated with its inhibitory effect on both the Akt and STAT3 signaling pathways. Keywords: Hispidulin, apoptosis, EMMPRIN, Akt, STAT3 Introduction AML patients will ultimately be diagnosed with relapsed or refractory disease despite cytotoxic Acute myeloid leukemia (AML), a hematologic chemotherapy [3, 4]. For AML patients who malignancy characterized by uncontrolled pro- relapse or have a resistant disease, therapeutic liferation and accumulation of myeloblasts in options are limited. The long-term overall sur- the bone marrow (BM), blood, and other organs, vival rates for AML patients <60 and ≥60 years represents a heterogeneous group of hemato- old are 30-40% and <10%, respectively, [5] logical neoplasms with marked heterogeneity which makes AML especially challenging; there- in response to both standard therapy and sur- fore, developing new therapeutic agents that vival [1]. The clinical outcomes of AML are very are less toxic and more specific to AML is unpredictable, from survival of a few days to imperative. the complete cure, depending on the age, biol- ogy, cytogenetic features, deregulated genes, Extracellular matrix metalloproteinase inducer and classification of the disease [2]. Standard (EMMPRIN), encoded by a gene localized to treatment options for AML are chemotherapy 19p13.3, is a cell-surface glycoprotein belong- and hematopoietic stem cell transplantation, ing to the immunoglobulin superfamily. EMM- which help ensure long-term, disease-free sur- PRIN has been implicated in many biological- vival for many patients; however, the majority of functions, including embryo implantation, sper- Hispidulin induces apoptosis in acute myeloid leukemia matogenesis [6], retinal development [7], were cultured in Roswell Park Memorial inflammation [8], wound healing [9], and tumor Institute (RPMI)-1640 medium (Gibco, MD, progression [10]. A number of studies have USA) supplemented with 10% fetal bovine shown that elevated EMMPRIN expression is serum (FBS; Gibco, MD, USA) and 1.0% associated with clinically aggressive behavior L-glutamine in a 5.0% CO2-humidified in- and poor prognoses in a variety of solid tumors cubator. [11-13], which might be associated with the inducing effect on the synthesis of matrix Primary culture of human acute myeloid leuke- metalloproteinase (MMP) in the surrounding mia cells stromal cells [14]. Within the context of hema- tological malignancy, Fu et al. [15] observed Leukemic blasts were obtained from eight AML elevated expressions of EMMPRIN in the BM patients (ranging from 35 to 65 years old) leukemia cells of patients with newly diagnosed undergoing routine diagnostic aspirations. All AML. Our previous study also showed that shR- patients provided written informed consent in NA-mediated EMMPRIN silencing inhibits AML accordance with the Declaration of Helsinki, U937 cell proliferation and increases chemo- and the study was approved by the Institutional sensitivity to Adriamycin, [16] which indicates Review Board of the University of Qingdao, that EMMPRIN might be a promising therapeu- College of Medicine, Shandong, China. Samples tic target in AML. were separated by centrifugation over Ficoll/ Hypaque (specific gravity: 1.077e1.081; Sigma- Hispidulin (4’,5,7-trihydroxy-6-methoxyflavone), Aldrich Corporation, Shanghai, China) at 400 g a naturally occurring flavonoid, is one of the at room temperature. The interface layer con- major active ingredients of the traditional taining the primarily blasts was removed using Chinese medicinal herb Salvia plebeia R. Br. a sterile Pasteur pipette and resuspended in [17, 18]. In vivo and in vitro studies have pro- medium containing 10% FBS. The purity of the vided evidence of the antifungal, anti-inflam- blast population was confirmed to be 80% by matory, antioxidant, antithrombotic, antiepilep- morphologic evaluation of Wright-stained cyto- tic, neuroprotective, and antiosteoporotic activ- spun cell preparations. Cells exhibiting >95% ities of this compound [19-22]. Recently, the viability by trypan blue exclusion were cultured antiproliferative effect of hispidulin has been in the presence of 50 ng/mL rhGM-CSF, 100 reported in human malignancies, including ng/mL rhIL-3, and 10 ng/mL rhG-CSF (Sigma- pancreatic, gastric, ovarian, and glioblastoma Aldrich Corporation, Shanghai, China). cancer in vitro [23-26]. Our previous results also demonstrated that hispidulin induces Primary culture of human peripheral blood apoptosis in hepatocellular carcinomacells [27] mononuclear and CD34+ mononuclear cells and we reported that hispidulin inhibits the pro- liferation and enhances the chemosensitivity of Peripheral blood mononuclear cells (PBMCs) of gallbladder cancer cells by targeting HIF-1α three healthy donors were isolated by centrifu- [28]; however, whether the antitumor effect of gation over lymphocyte separation medium hispidulin in a solid tumor can be replicated in (Sigma-Aldrich Corporation, Shanghai, China). hematological malignancies has never been The study protocol was reviewed and approved studied. Hence, the present study was conduct- by the Institutional Review Board of the ed to investigate the effects of hispidulin on the University of Qingdao, College of Medicine. human leukemia cell line in vitro and the under- Written informed consent was obtained from lying mechanisms for its action on these cells. each participant. After three washes in phos- phate-buffered saline (PBS), PBMCs were Materials and methods counted and cultured in Dulbecco’s modified Eagle’s medium supplemented with 10% FBS, Cell lines and cultures 2.0 mg phytohemagglutinin per mL, 10 ng phorbol 12-myristate-13-acetate per mL, non- Human AML U937 and HL-60 cell lines were essential amino acids, 5.0 mM b-mercaptoeth- obtained from the Shanghai Institutes for anol, 10 mM 2-hydroxyethyl-1-piperazineethan- Biological Science (Shanghai, China). Cells esulfonic acid (HEPES), 2.0 mM glutamine, and 1116 Am J Transl Res 2016;8(2):1115-1132 Hispidulin induces apoptosis in acute myeloid leukemia 1.0 mM sodium pyruvate (all purchased from trypan blue stain divided by the number of total Sigma-Aldrich Corporation, Shanghai, China). cells. BM aspirates were obtained from three volun- teer donors using protocols approved by the Cell-cycle analysis Institutional Review Board of the University of Cell-cycle analysis was conducted 48 h after Qingdao, College of Medicine. Following transfection using the Cell Cycle and Apoptosis + informed consent, CD34 cells were extracted Analysis Kit (Beyotime, Shanghai, China) follow- using immunomagnetic beads conjugated with ing the manufacturer’s instructions. Briefly, an anti-CD34 antibody (ThermoFisher, Norway, cells were collected and fixed with 70% cold 11301D) following the manufacturer’s instru- ethanol at 4.0°C overnight. DNA was stained ctions. with 0.05 mg/mL propidium iodide and 2.0 mg/mL RNase for 30 min at room temperature. In vitro proliferation assay Cells were then subjected to a FACScan cytom- In vitro proliferation was determined by etry (Beckman Coulter Inc., Miami, FL, USA) for 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetra- cell-cycle analysis. The percentage of cells in zolium bromide (MTT) assay (Sigma-Aldrich G0/G1, S, and G2/M phases of the cell cycle Corporation, St. Louis, MO, USA). Briefly, cells was calculated using Cell Lab Quanta SC were plated at a density of 5.0 × 103 cells/well software. in 96-well culture plates. After treatment, 20 µL Cell apoptosis analysis MTT solution (5.0 mg/mL in PBS) were added to each well and
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