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      TRAIL combinations: The new ‘trail’ for cancer therapy (Review)

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          Abstract

          Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) therapy is anticipated to be one of the most effective cancer treatments. However, resistance to TRAIL therapy remains a challenge facing the development of anticancer strategies. To circumvent this problem, TRAIL combinations have been experimented with for over ten years to induce synergism or sensitize resistant cancer cells. By analyzing the signaling pathways triggered by these combinations, this review has defined a set of core targets for novel combinatorial treatments. The review suggests specific pathways to be targeted together with TRAIL for more efficient treatment, including cellular FLICE inhibitory protein and its downstream survival factors, the Bcl-2 family and other prominent targets. The suggested pathways provide new avenues for more effective TRAIL-based cancer therapy.

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          Extrinsic versus intrinsic apoptosis pathways in anticancer chemotherapy.

          S Fulda, K-M Debatin (2006)
          Apoptosis or programmed cell death is a key regulator of physiological growth control and regulation of tissue homeostasis. One of the most important advances in cancer research in recent years is the recognition that cell death mostly by apoptosis is crucially involved in the regulation of tumor formation and also critically determines treatment response. Killing of tumor cells by most anticancer strategies currently used in clinical oncology, for example, chemotherapy, gamma-irradiation, suicide gene therapy or immunotherapy, has been linked to activation of apoptosis signal transduction pathways in cancer cells such as the intrinsic and/or extrinsic pathway. Thus, failure to undergo apoptosis may result in treatment resistance. Understanding the molecular events that regulate apoptosis in response to anticancer chemotherapy, and how cancer cells evade apoptotic death, provides novel opportunities for a more rational approach to develop molecular-targeted therapies for combating cancer.
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            Phosphatase-mediated crosstalk between MAPK signaling pathways in the regulation of cell survival.

            Melissa Junttila, Song-Ping Li, Jukka Westermarck (2008)
            Mitogen-activated protein kinase (MAPK) pathways constitute a large modular network that regulates a variety of physiological processes, such as cell growth, differentiation, and apoptotic cell death. The function of the ERK pathway has been depicted as survival-promoting, in essence by opposing the proapoptotic activity of the stress-activated c-Jun NH(2)-terminal kinase (JNK)/p38 MAPK pathways. However, recently published work suggests that extracellular regulated kinase (ERK) pathway activity is suppressed by JNK/p38 kinases during apoptosis induction. In this review, we will summarize the current knowledge about JNK/p38-mediated mechanisms that negatively regulate the ERK pathway. In particular, we will focus on phosphatases (PP2A, MKPs) as inhibitors of ERK pathway activity in regulating apoptosis. A model proposed in this review places the negative regulation of the ERK pathway in a central position for the cellular decision-making process that determines whether cells will live or die in response to apoptosis-promoting signals. In addition, we will discuss the potential functional relevance of negative regulation of ERK pathway activity, for physiological and pathological conditions (e.g., cellular transformation).
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              Structure-based discovery of an organic compound that binds Bcl-2 protein and induces apoptosis of tumor cells.

              Srinivasa M Srinivasula, Gang Zhang, X. Han … (2000)
              Bcl-2 and related proteins are key regulators of apoptosis or programmed cell death implicated in human disease including cancer. We recently showed that cell-permeable Bcl-2 binding peptides could induce apoptosis of human myeloid leukemia in vitro and suppress its growth in severe combined immunodeficient mice. Here we report the discovery of HA14-1, a small molecule (molecular weight = 409) and nonpeptidic ligand of a Bcl-2 surface pocket, by using a computer screening strategy based on the predicted structure of Bcl-2 protein. In vitro binding studies demonstrated the interaction of HA14-1 with this Bcl-2 surface pocket that is essential for Bcl-2 biological function. HA14-1 effectively induced apoptosis of human acute myeloid leukemia (HL-60) cells overexpressing Bcl-2 protein that was associated with the decrease in mitochondrial membrane potential and activation of caspase-9 followed by caspase-3. Cytokine response modifier A, a potent inhibitor of Fas-mediated apoptosis, did not block apoptosis induced by HA14-1. Whereas HA14-1 strongly induced the death of NIH 3T3 (Apaf-1(+/+)) cells, it had little apoptotic effect on Apaf-1-deficient (Apaf-1(-/-)) mouse embryonic fibroblast cells. These data are consistent with a mechanism by which HA14-1 induces the activation of Apaf-1 and caspases, possibly by binding to Bcl-2 protein and inhibiting its function. The discovery of this cell-permeable molecule provides a chemical probe to study Bcl-2-regulated apoptotic pathways in vivo and could lead to the development of new therapeutic agents.
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                Author and article information

                Journal
                Journal ID (nlm-ta): Oncol Lett
                Journal ID (iso-abbrev): Oncol Lett
                Journal ID (publisher-id): OL
                Title: Oncology Letters
                Publisher: D.A. Spandidos
                ISSN (Print): 1792-1074
                ISSN (Electronic): 1792-1082
                Publication date (Print): May 2014
                Publication date (Electronic): 27 February 2014
                Publication date PMC-release: 27 February 2014
                Volume: 7
                Issue: 5
                Pages: 1327-1332
                Affiliations
                Center for Aging and Associated Diseases, Zewail City of Science and Technology, Giza 12588, Egypt
                Author notes
                Correspondence to: Dr Alaa Refaat, Center for Aging and Associated Diseases, Zewail City of Science and Technology, Sheikh Zayed, 6th of October City, Giza 12588, Egypt, E-mail: arefaat@ 123456zewailcity.edu.eg
                Article
                Publisher ID: ol-07-05-1327
                DOI: 10.3892/ol.2014.1922
                PMC ID: 3997674
                PubMed ID: 24765133
                SO-VID: fb1af42c-6c58-4c7e-b8bb-75e41af6f373
                Copyright © Copyright © 2014, Spandidos Publications
                License:

                This is an open-access article licensed under a Creative Commons Attribution-NonCommercial 3.0 Unported License. The article may be redistributed, reproduced, and reused for non-commercial purposes, provided the original source is properly cited.

                History
                Date received : 22 July 2013
                Date accepted : 21 January 2014
                Categories
                Subject: Articles

                ScienceOpen disciplines: Oncology & Radiotherapy
                Keywords: tumor necrosis factor related apoptosis-inducing ligand,death receptor 5,apoptosis,cancer therapy
                Data availability:
                ScienceOpen disciplines: Oncology & Radiotherapy
                Keywords: tumor necrosis factor related apoptosis-inducing ligand, death receptor 5, apoptosis, cancer therapy

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