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      Simultaneous use of erythropoietin and LFM‐A13 as a new therapeutic approach for colorectal cancer

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          Abstract

          Background and Purpose

          Bruton's tyrosine kinase (Btk) is a non‐receptor tyrosine kinase involved in the activation of signalling pathways responsible for cell maturation and viability. Btk has previously been reported to be overexpressed in colon cancers. This kind of cancer is often accompanied by anaemia, which is treated with an erythropoietin supplement. The goal of the present study was to assess the effects of combination therapy with erythropoietin β (Epo) and LFM‐A13 (Btk inhibitor) on colon cancer in in vitro and in vivo models.

          Experimental Approach

          DLD‐1 and HT‐29 human colon adenocarcinoma cells were cultured with Epo and LFM‐A13. Cell number and viability, and mRNA and protein levels of Epo receptors, Btk and Akt were assessed. Nude mice were inoculated with adenocarcinoma cells and treated with Epo and LFM‐A13.

          Key Results

          The combination of Epo and LFM‐A13 mostly exerted a synergistic inhibitory effect on colon cancer cell growth. The therapeutic scheme used effectively killed the cancer cells and attenuated the Btk signalling pathways. Epo + LFM‐A13 also prevented the normal process of microtubule assembly during mitosis by down‐regulating the expression of Polo‐like kinase 1. The combination of Epo and LFM‐A13 significantly reduced the growth rate of tumour cells, while it showed high safety profile, inducing no nephrotoxicity, hepatotoxicity or changes in the haematological parameters.

          Conclusion and Implications

          Epo significantly enhances the antitumour activity of LFM‐A13, indicating that a combination of Epo and LFM‐A13 has potential as an effective therapeutic approach for patients with colorectal cancer.

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          Most cited references 48

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          Quantitative analysis of dose-effect relationships: the combined effects of multiple drugs or enzyme inhibitors.

           P Talalay,  T C Chou (1984)
          A generalized method for analyzing the effects of multiple drugs and for determining summation, synergism and antagonism has been proposed. The derived, generalized equations are based on kinetic principles. The method is relatively simple and is not limited by whether the dose-effect relationships are hyperbolic or sigmoidal, whether the effects of the drugs are mutually exclusive or nonexclusive, whether the ligand interactions are competitive, noncompetitive or uncompetitive, whether the drugs are agonists or antagonists, or the number of drugs involved. The equations for the two most widely used methods for analyzing synergism, antagonism and summation of effects of multiple drugs, the isobologram and fractional product concepts, have been derived and been shown to have limitations in their applications. These two methods cannot be used indiscriminately. The equations underlying these two methods can be derived from a more generalized equation previously developed by us (59). It can be shown that the isobologram is valid only for drugs whose effects are mutually exclusive, whereas the fractional product method is valid only for mutually nonexclusive drugs which have hyperbolic dose-effect curves. Furthermore, in the isobol method, it is laborious to find proper combinations of drugs that would produce an iso-effective curve, and the fractional product method tends to give indication of synergism, since it underestimates the summation of the effect of mutually nonexclusive drugs that have sigmoidal dose-effect curves. The method described herein is devoid of these deficiencies and limitations. The simplified experimental design proposed for multiple drug-effect analysis has the following advantages: It provides a simple diagnostic plot (i.e., the median-effect plot) for evaluating the applicability of the data, and provides parameters that can be directly used to obtain a general equation for the dose-effect relation; the analysis which involves logarithmic conversion and linear regression can be readily carried out with a simple programmable electronic calculator and does not require special graph paper or tables; and the simplicity of the equation allows flexibility of application and the use of a minimum number of data points. This method has been used to analyze experimental data obtained from enzymatic, cellular and animal systems.
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            Bruton tyrosine kinase represents a promising therapeutic target for treatment of chronic lymphocytic leukemia and is effectively targeted by PCI-32765.

            B-cell receptor (BCR) signaling is aberrantly activated in chronic lymphocytic leukemia (CLL). Bruton tyrosine kinase (BTK) is essential to BCR signaling and in knockout mouse models its mutation has a relatively B cell-specific phenotype. Herein, we demonstrate that BTK protein and mRNA are significantly over expressed in CLL compared with normal B cells. Although BTK is not always constitutively active in CLL cells, BCR or CD40 signaling is accompanied by effective activation of this pathway. Using the irreversible BTK inhibitor PCI-32765, we demonstrate modest apoptosis in CLL cells that is greater than that observed in normal B cells. No influence of PCI-32765 on T-cell survival is observed. Treatment of CD40 or BCR activated CLL cells with PCI-32765 results in inhibition of BTK tyrosine phosphorylation and also effectively abrogates downstream survival pathways activated by this kinase including ERK1/2, PI3K, and NF-κB. In addition, PCI-32765 inhibits activation-induced proliferation of CLL cells in vitro, and effectively blocks survival signals provided externally to CLL cells from the microenvironment including soluble factors (CD40L, BAFF, IL-6, IL-4, and TNF-α), fibronectin engagement, and stromal cell contact. Based on these collective data, future efforts targeting BTK with the irreversible inhibitor PCI-32765 in clinical trials of CLL patients is warranted.
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              Positive feedback of G1 cyclins ensures coherent cell cycle entry.

              In budding yeast, Saccharomyces cerevisiae, the Start checkpoint integrates multiple internal and external signals into an all-or-none decision to enter the cell cycle. Here we show that Start behaves like a switch due to systems-level feedback in the regulatory network. In contrast to current models proposing a linear cascade of Start activation, transcriptional positive feedback of the G1 cyclins Cln1 and Cln2 induces the near-simultaneous expression of the approximately 200-gene G1/S regulon. Nuclear Cln2 drives coherent regulon expression, whereas cytoplasmic Cln2 drives efficient budding. Cells with the CLN1 and CLN2 genes deleted frequently arrest as unbudded cells, incurring a large fluctuation-induced fitness penalty due to both the lack of cytoplasmic Cln2 and insufficient G1/S regulon expression. Thus, positive-feedback-amplified expression of Cln1 and Cln2 simultaneously drives robust budding and rapid, coherent regulon expression. A similar G1/S regulatory network in mammalian cells, comprised of non-orthologous genes, suggests either conservation of regulatory architecture or convergent evolution.
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                Author and article information

                Contributors
                aniatan@poczta.onet.pl
                Journal
                Br J Pharmacol
                Br. J. Pharmacol
                10.1111/(ISSN)1476-5381
                BPH
                British Journal of Pharmacology
                John Wiley and Sons Inc. (Hoboken )
                0007-1188
                1476-5381
                25 January 2018
                March 2018
                25 January 2018
                : 175
                : 5 ( doiID: 10.1111/bph.v175.5 )
                : 743-762
                Affiliations
                [ 1 ] Department of Monitored Pharmacotherapy Medical University of Bialystok Bialystok Poland
                [ 2 ] Department of Pharmacodynamics Medical University of Bialystok Bialystok Poland
                [ 3 ] Department of Clinical Pharmacy Medical University of Bialystok Bialystok Poland
                [ 4 ] Department of Hematological Diagnostics Medical University of Bialystok Bialystok Poland
                [ 5 ] Department of Pathomorphology Medical University of Bialystok Bialystok Poland
                [ 6 ] Department of Medicinal Chemistry Medical University of Bialystok Bialystok Poland
                Author notes
                [* ] Correspondence

                Anna Tankiewicz‐Kwedlo, Department of Monitored Pharmacotherapy, Medical University of Bialystok, Mickiewicza 2C, 15‐222 Bialystok, Poland. E‐mail: aniatan@ 123456poczta.onet.pl

                Article
                BPH14099 2017-BJP-0336-RP.R1
                10.1111/bph.14099
                5811618
                29160911
                © 2017 The Authors. British Journal of Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.

                This is an open access article under the terms of the Creative Commons Attribution‐NonCommercial License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.

                Page count
                Figures: 6, Tables: 1, Pages: 20, Words: 8861
                Product
                Funding
                Funded by: National Science Centre, Poland
                Award ID: DEC‐2017/01/X/NZ5/00362
                Funded by: Leading National Science Centre in Bialystok
                Award ID: 122/KNOW/2015
                Funded by: Medical University of Bialystok
                Award ID: N/ST/MN/17/001/2233
                Award ID: N/ST/ZB/17/001/2228
                Award ID: POPW.01.03.00‐20‐022/09
                Categories
                Research Paper
                Research Papers
                Custom metadata
                2.0
                bph14099
                March 2018
                Converter:WILEY_ML3GV2_TO_NLMPMC version:version=5.3.2.2 mode:remove_FC converted:14.02.2018

                Pharmacology & Pharmaceutical medicine

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