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      Synergistic induction of apoptosis in a cell model of human leukemia K562 by nitroglycerine and valproic acid

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          Abstract

          Nitroglycerin (NG), a nitric oxide donor, and valproic acid (VPA), an inhibitor of histone deacetylases, have impressive effects on numerous cancer cell lines. This study intended to evaluate synergistic effects of NG and VPA on cell viability and apoptosis in K562 cells. K562 cells were cultured in RPMI-1640 supplemented with 10 % heat-inactivated FBS. They were treated with different doses of NG, VPA and cisplatin for 24, 48, and 72 h, and MTT assay was performed to analyze cell viability. Also, Peripheral blood mononuclear cells (PBMC) were cultured in RPMI-1640 media and incubated with NG (200 μM), VAP (100 μM), NG+VPA (150 μM) and cisplatin (8 μM) to evaluate cytotoxicity. IC 50 of the drugs, when they were applied separately and in combination, were calculated using the COMPUSYN software. DNA electrophoresis, TUNEL assay, and Hoechst staining were performed to investigate apoptosis induction. RT-PCR was used for the evaluation of apoptotic genes expression. The results of the MTT assay showed that cell viability decreased at all applied doses of NG and VPA. It was noticed that the cytotoxic effects of these drugs were dose- and time-dependent. Based on the COMPUSYN output, the combination of the drugs (VPA and NG) in a certain ratio concentration synergistically decreased cell viability. Cisplatin significantly decreased cell viability of PBMCs and K562 cells. Also, the combination drug had cytotoxic effect and significantly reduced viability of K562 cells compared with PBMCs and control cells. In the target cells treated with this combination, Bax and caspase-3 expression increased but Bcl-2 expression decreased. These results suggest that NG, VPA, and their combination decreased cell viability and induced apoptosis via the intrinsic apoptotic pathway. This study suggests that this combination therapy can be considered for further evaluation as an effective chemotherapeutic strategy for patients with chronic myeloid leukemia.

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          Nitric Oxide Donor-Based Cancer Therapy: Advances and Prospects.

          Zhangjian Huang, Junjie Fu, Yihua Zhang (2017)
          The increasing understanding of the role of nitric oxide (NO) in cancer biology has generated significant progress in the use of NO donor-based therapy to fight cancer. These advances strongly suggest the potential adoption of NO donor-based therapy in clinical practice, and this has been supported by several clinical studies in the past decade. In this review, we first highlight several types of important NO donors, including recently developed NO donors bearing a dinitroazetidine skeleton, represented by RRx-001, with potential utility in cancer therapy. Special emphasis is then given to the combination of NO donor(s) with other therapies to achieve synergy and to the hybridization of NO donor(s) with an anticancer drug/agent/fragment to enhance the activity or specificity or to reduce toxicity. In addition, we briefly describe inducible NO synthase gene therapy and nanotechnology, which have recently entered the field of NO donor therapy.
          Article 0 comments Cited 75 times – based on 0 reviews     Review now
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            Analysis of apoptosis by cytometry using TUNEL assay.

            Zbigniew Darzynkiewicz, Dariusz Galkowski, Hong Yang Zhao (2008)
            Activation of endonucleases that cleave chromosomal DNA preferentially at internucleosomal sections is a hallmark of apoptosis. DNA fragmentation revealed by the presence of a multitude of DNA strand breaks, therefore, is considered to be the gold standard for identification apoptotic cells. Several variants of the methodology that is based on fluorochrome-labeling of 3'-OH termini of DNA strand breaks in situ with the use of exogenous terminal deoxynucleotidyl transferase (TdT), commonly defined as the TUNEL assay, have been developed by us. This Chapter describes the variant based on strand breaks labeling with Br-dUTP that is subsequently detected immunocytochemically with Br-dUAb. Compared with other TUNEL variants the Br-dU-labeling assay offers the greatest sensitivity in detecting DNA breaks. Described also are modifications of the protocol that allow one to use other than Br-dUTP fluorochrome-tagged deoxynucleotides to label DNA breaks. Concurrent staining of DNA with propidium or 4',6-diamidino-2-phenylindole (DAPI) and multiparameter analysis of cells by flow- or laser scanning cytometry enables one to correlate induction of apoptosis with the cell cycle phase.
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              Synergistic combination of microtubule targeting anticancer fludelone with cytoprotective panaxytriol derived from panax ginseng against MX-1 cells in vitro: experimental design and data analysis using the combination index method.

              Ning Zhang, Jia-Ning Fu, Ting-Chao Chou (2016)
              This brief article focuses on two aims: i) To investigate the in vitro pharmaco-dynamic interactions of combining synthetic potent microtubule targeting anticancer agent, Fludelone (FD) with cyto-protective agent, Panaxytriol (PXT) derived from Panax ginseng, and ii) To illustrate step-by-step operation for conducting two-drug combination in vitro using the combination index method, in terms of experimental design, data acquisition, computerized simulation and data interpretation. The Chou-Talalay method for drug combination is based on the median-effect equation, which provides the theoretical basis for the combination index (CI)-isobologram equation that allows quantitative determination of drug interactions, where CI 1 indicates synergism, additive effect and antagonism, respectively. Based on these algorithms, computer software, CompySyn, is used for determining synergism and antagonism at all doses or effect levels simulated automatically. The use of Chou-Talalay's CI method in quantifying synergism or antagonism is increasing steadily during the past two decades, however, confusing questions and pitfalls were still frequently raised by insufficient understanding of the theory, especially reflected when researchers trying to use the computerized software to design and conduct experiments. In order to specifically address the confusions and to illustrate the practical features of this method, in this paper, a selected example is given based on our unpublished data regarding the combinational pharmacologic interactions of FD and PXT against the growth of breast cancer cell line MX-1. The step-by-step operation from experimental design to the real data analysis is illustrated. The results indicated that FD and PXT combination in vitro exerted synergistic effect when cell growth inhibition was greater than 45%, with CI ranged 0.836-0.609 for the fractional inhibition of Fa=0.50~0.90, as shown by the Fa-CI plot and by the isobologram. Thus, quantitative conclusion of synergism is obtained using the Chou-Talalay CI method, under the well-defined simple conditions for the FD and PXT combinations in vitro.
              Article 0 comments Cited 67 times – based on 0 reviews     Review now
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                Author and article information

                Journal
                Journal ID (nlm-ta): EXCLI J
                Journal ID (iso-abbrev): EXCLI J
                Journal ID (publisher-id): EXCLI J
                Title: EXCLI Journal
                Publisher: Leibniz Research Centre for Working Environment and Human Factors
                ISSN (Electronic): 1611-2156
                Publication date (Electronic): 15 August 2019
                Publication date Collection: 2019
                Volume: 18
                Pages: 619-630
                Affiliations
                [1 ]Department of Biology, Faculty of Sciences, Urmia University, Urmia, Iran
                Author notes
                *To whom correspondence should be addressed: Mehdi Mohammadzadeh, Nazlou Campus, Urmia University, 11 km of Nazlou Road, Urmia, Iran, Postal Code: 5756151818; P.O. Box: 165; Tel: +989143492661, Fax: +984432753172, E-mail: m.mohamadzade@ 123456urmia.ac.ir
                Article
                Publisher ID: 2019-1581 Publisher ID: Doc619
                DOI: 10.17179/excli2019-1581
                PMC ID: 6785758
                PubMed ID: 31611745
                SO-VID: a36182b5-7887-4afd-8438-35f93109c8e2
                Copyright © Copyright © 2019 Aalaei et al.
                License:

                This is an Open Access article distributed under the terms of the Creative Commons Attribution Licence ( http://creativecommons.org/licenses/by/4.0/) You are free to copy, distribute and transmit the work, provided the original author and source are credited.

                History
                Date received : 28 June 2019
                Date accepted : 31 July 2019
                Categories
                Subject: Original Article

                Keywords: apoptosis,combination therapy,cytotoxicity,k562 cells,nitroglycerine,valproic acid
                Data availability:
                Keywords: apoptosis, combination therapy, cytotoxicity, k562 cells, nitroglycerine, valproic acid

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