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E of extreme importance. 2-Methoxyestradiol (2ME) (Figure 1) is a metabolite of 17-estradiol which has been 2-(2,4-Dichloro-5-fluorophenyl)oxirane tested for its antitumour and antiangiogenic properties in vitro and in vivo [2,3]. 2ME however, has poor bioavailability limiting the action in vivo as indicated in earlier phase I studies where* Correspondence: annie.joubert@up.ac.za Department of Physiology, School of Medicine, Faculty of Health Sciences, University of Pretoria, Pretoria, South Africa2ME was orally administered to cancer patients in the form of a capsule [5]. The rate at which 2ME becomes available to the site of drug action is low since the rate of oxidation of 2ME is higher than absorption [5]. 2ME is rapidly oxidized in the gastrointestinal tract when orally administered by the enzyme 17-hydroxysteriod dehydrogenase [6,7]. This leads to decreased levels of 2ME, thus being too low to exert significant antitumour effects [8]. The development of a 2ME NanoCrystal?colloidal dispersion (NCD) was subsequently formulated. The latter increased bioavailability, however, the antitumour effects were not optimal in patients [9]. This led to the development and synthesis of analogues of 2ME?2014 Repsold et al.; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms 1-(4-Bromo-2-pyridyl)piperazine of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.Repsold et al. Cancer Cell International 2014, 14:48 http://www.cancerci.com/content/14/1/Page 2 ofFigure 1 Structure of 2-methoxyestradiol [4].to journal.pone.0167038 test for a compound with increased antitumour and antiangiogenic properties with increased bioavailability [10,11]. Such analogues of 2ME have been in silicodesigned in our laboratory (Figure 2). One novel in silicodesigned analogue is 2-ethyl-3-O-sulphamoyl-estra-1, 3, 5 (10)16-tetraene (ESE-16) (Figure 2). 2ME exerts its anticancer signaling PubMed ID:https://www.ncbi.nlm.nih.gov/pubmed/13485127 by disrupting mitochondrial function, generating reactive oxygen species (ROS) and by targeting microtubule dynamics in vitro and in vivo [13]. 2ME results in apoptosis involving both the extrinsic and intrinsic pathways [14]. 2ME activates apoptosis via the extrinsic pathway by means of deathreceptors (DRs) such as death receptor 5 (DR5) and activates caspases known to PubMed ID:https://www.ncbi.nlm.nih.gov/pubmed/13485127 promote the extrinsic pathway [14]. The extrinsic pathway of apoptosis comprises of the instigation of caspase 8, caspase 3, and upregulation of DR5 with activation of caspase 9 present in the intrinsic pathway through crosstalk with caspase 8 [14,15]. Production of ROS in 2ME- and analogue-treated cells is likely to be a result of the inhibition of the mitochondrial electron transport complex I [13] leading to autophagy by means of beclin-1 upregulation and autophagy protein 4 (Atg4) inactivation [16]. Generation of ROS upregulates beclin-1 which results in the increased incidence of autophagy, while hydrogen peroxide causes autophagy and the inactivation of Atg4 responsible for the induction of autophagy [17]. 2ME also induces apoptosis in cancer cells as a result of the upregulation of p53, since p53 is known to arbitrate cell cycle arrest that may lead to the induction of apoptosis by controlling the G2/M cell cycle checkpoint [18,19].