Cancer Cell International | |
An estrogen analogue and promising anticancer agent refrains from inducing morphological damage and reactive oxygen species generation in erythrocytes, fibrin and platelets: a pilot study | |
Annie Margaretha Joubert1  Etheresia Pretorius1  Lisa Repsold1  | |
[1] Department of Physiology, School of Medicine, Faculty of Health Sciences, University of Pretoria, Pretoria, South Africa | |
关键词: Cancer; Reactive oxygen species; 5(10)16-tetraene; 3; 2-Ethyl-3-O-sulphamoyl-estra-1; 2-Methoxyestradiol analogues; | |
Others : 791891 DOI : 10.1186/1475-2867-14-48 |
|
received in 2014-03-28, accepted in 2014-05-26, 发布年份 2014 | |
【 摘 要 】
Background
2-Methoxyestradiol is known to have antitumour and antiproliferative action in vitro and in vivo. However, when 2-methoxyestradiol is orally administered, it is rapidly oxidized by the enzyme 17β-hydroxysteriod dehydrogenase in the gastrointestinal tract. Therefore, 2-methoxyestradiol never reaches high enough concentrations in the tissue to be able to exert these antitumour properties. This resulted in the in silico-design of 2-methoxyestradiol analogues in collaboration with the Bioinformatics and Computational Biology Unit (UP) and subsequent synthesis by iThemba Pharmaceuticals (Pty) Ltd (Modderfontein, Midrand, South Africa). One such a novelty-designed analogue is 2-ethyl-3-O-sulphamoyl-estra-1, 3, 5(10)16-tetraene (ESE-16).
Methods
This pilot study aimed to determine the morphological effect and possible generation of reactive oxygen species by ESE-16 on erythrocytes and platelet samples (with and without added thrombin) by means of scanning electron microscopy, transmission electron microscopy and flow cytometry.
Results
Erythrocytes and platelets were exposed to ESE-16 at a concentration of 180nM for 24Â hours. Scanning- and transmission electron microscopy indicated that ESE-16 did not cause changes to erythrocytes, platelets or fibrin networks. Flow cytometry measurements of hydrogen peroxide and superoxide indicated that ESE-16 does not cause an increase in the generation of reactive oxygen species in these blood samples.
Conclusion
Further in vivo research is warranted to determine whether this novel in silico-designed analogue may impact on development of future chemotherapeutic agents and whether it could be considered as an antitumour agent.
【 授权许可】
2014 Repsold et al.; licensee BioMed Central Ltd.
【 预 览 】
Files | Size | Format | View |
---|---|---|---|
20140705022441155.pdf | 1829KB | download | |
Figure 5. | 72KB | Image | download |
Figure 4. | 81KB | Image | download |
Figure 3. | 166KB | Image | download |
Figure 2. | 58KB | Image | download |
Figure 1. | 39KB | Image | download |
【 图 表 】
Figure 1.
Figure 2.
Figure 3.
Figure 4.
Figure 5.
【 参考文献 】
- [1]Siegel R, Naishadham D, Jema A: Cancer statistics, 2012. CA Cancer J Clin 2012, 62:10-29.
- [2]Fukui M, Zhu BT: Mechanism of 2-methoxyestradiol-induced apoptosis and growth arrest in human breast cancer cells. Mol Carcinog 2009, 48:66-78.
- [3]Du B, Zhao Z, Sun H, Ma S, Jin J, Zhang Z: Effects of 2-methoxyestradiol on proliferation, apoptosis and gene expression of cyclin B1 and c-Myc in esophageal carcinoma EC9706 cells. Cell Biochem Funct 2012, 30:158-165.
- [4]Cayman Chemical [homepage on the internet]: Michigan: Cayman Chemical Company; [cited 2012 Mar 27]. 2-Methoxyestradiol; [about 2 screens]. 2012. http://www.caymanchem.com/app/template/Product.vm/catalog/13021 webcite
- [5]Balant LP: Is there a need for more precise definitions of bioavailability? Eur J Clin Pharmacol 1991, 40:123-126.
- [6]Mqoco T, Marais S, Joubert A: Influence of estradiol analogue on cell growth, morphology and death in esophageal carcinoma cells. Biocell 2010, 34(Suppl 3):113-120.
- [7]Foster PA, Ho YT, Newman SP, Kasprzyk G, Leese MP, Potter BVL, Reed MJ, Purohit A: 2-MeOE2bisMATE and 2-EtE2bisMATE induce cell cycle arrest and apoptosis in breast cancer xenografts as shown by a novel ex vivo technique. Breast Cancer Res Treat 2008, 111:251-260.
- [8]Stander BA, Marais S, Vorster CJJ, Joubert AM: In vitro effects of 2-methoxyestradiol on morphology, cell cycle progression, cell death and gene expression changes in the tumorigenic MCF-7 breast epithelial cell line. J Steroid Biochem Mol Biol 2010, 119:149-160.
- [9]Zhou Q, Gustafson D, Nallapareddy S, Diab S, Leong S, Lewis K, Gore L, Messersmith WA, Treston AM, Eckhardt SG, Sidor C, Camidge DR: A phase I dose-escalation, safety and pharmacokinetic study of the 2-methoxyestradiol analog ENMD-1198 administered orally to patients with advanced cancer. Invest New Drugs 2011, 29:340-346.
- [10]Joubert A, Marais S: Influence of 2-methoxyestradiol on cell morphology and Cdc2 kinase activity in WHCO3 esophageal carcinoma cells. Biomed Res 2007, 28:9-16.
- [11]Maran A, Gorny G, Oursler MJ, Zhang M, Shogren KL, Yaszemski MJ, Turner RT: 2-methoxyestradiol inhibits differentiation and is cytotoxic to osteoclasts. J Cell Biochem 2006, 99:425-434.
- [12]Stander A, Joubert F, Joubert A: Docking, synthesis, and in vitro evaluation of antimitotic estrone analogs. Chem Biol Drug Des 2011, 77:173-181.
- [13]Chua YS, Chua YL, Hagen T: Structure activity analysis of 2-methoxyestradiol analogues reveals targeting of microtubules as the major mechanism of antiproliferative and propapoptotic activity. Mol Cancer Ther 2010, 9:224-235.
- [14]LaVallee TM, Zhan XH, Johnson MS, Herbstritt CJ, Swartz G, Williams MS, Hembrough WA, Green SJ, Pribluda VS: 2-Methoxyestradiol up-regulates death receptor 5 and induces apoptosis through activation of the extrinsic pathway. Cancer Res 2003, 63:468-475.
- [15]Zhang Q, Ma Y, Cheng YF, Li WJ, Zhang Z, Chen S: Involvement of reactive oxygen species in 2-methoxyestradiol-induced apoptosis in human neuroblastoma cells. Cancer Lett 2011, 313:201-210.
- [16]Azad MB, Chen Y, Gibson SB: Regulation of autophagy by reactive oxygen species (ROS): implications for cancer progression and treatment. Antioxid Redox Signal 2009, 11(Suppl 4):777-790.
- [17]Visagie MH, Joubert AM: In vitro effects of 2-methoxyestradiol-bis-sulphamate on reactive oxygen species and possible apoptosis induction in a breast adenocarcinoma cell line. Cancer Cell Int 2011, 11:43. BioMed Central Full Text
- [18]Seegers JC, Lottering ML, Grobler CJS, Van Papendorp DH, Habbersett RC, Shou Y, Lehnert BE: The mammalian metabolite, 2-methoxyestradiol, affects p53 levels and apoptosis induction in transformed cells but not in normal cells. J Steroid Biochem Mol Biol 1997, 62(Suppl 4):253-267.
- [19]Mukhopadhyay T, Roth JA: Induction of apoptosis in human lung cancer cells after wild-type p53 activation by methoxyestradiol. Oncogene 1997, 14:379-384.
- [20]Thaver V, Lottering ML, van Papendorp D, Joubert A: In vitro effects of 2-methoxyestradiol on cell numbers, morphology, cell cycle progression, and apoptosis induction in oesophageal carcinoma cells. Cell Biochem Funct 2009, 27:205-210.
- [21]Li L, Bu S, Bäckström T, Landström M, Ulmsten U, Fu X: Induction of apoptosis and G2/M arrest by 2-methoxyestradiol in human cervical cancer HeLaS3 cells. Anticancer Res 2004, 24:873-880.
- [22]Pasquier E, Kavallaris M: Microtubules: A dynamic target in cancer therapy. IUBMB Life 2008, 60(Suppl 3):165-170.
- [23]Dobos J, Timar J, Bocsi J, Burian Z, Nagy K, Barna G, Peták I, Ladányi : In vitro and In vivo antitumour effect of 2- methoxyestradiol on human melanoma. Int J Cancer 2004, 112:771-776.
- [24]Vorster C, Joubert A: In vitro effects of 2-methoxyestradiol-bis-sulphamate on cell growth, morphology and cell cycle dynamics in the MCF-7 breast adenocarcinoma cell line. Biocell 2010, 34(Suppl 2):71-79.
- [25]Choi HJ, Zhu BT: Critical role of cyclin B1/Cdc2 up-regulation in the induction of mitotic prometaphase arrest in human breast cancer cells treated with 2-methoxyestradiol. Biochim Biophys Acta 1823, 2012:1306-1315.
- [26]Stander XX, Stander BA, Joubert AM: In vitro effects of an in silico modelled 17β-estradiol derivative in combination with dichloroacetic acid on MCF-7 and MCF-12A cells. Cell Prolif 2011, 44:567-581.
- [27]Van Zijl C, Lottering ML, Steffens F, Joubert A: In vitro effects of 2-methoxyestradiol on MCF-12A and MCF-7 cell growth, morphology and mitotic spindle formation. Cell Biochem Funct 2008, 26:632-642.
- [28]Visagie MH, Joubert AM: 2-Methoxyestradiol-bis-sulfamate induces apoptosis and autophagy in a tumorigenic breast epithelial cell line. Mol Cell Biochem 2011, 357:343-352.
- [29]Stander BA, Joubert F, Tu C, Sippel KH, McKenna R, Joubert AM: Signaling pathways of ESE-16, an antimitotic and anticarbonic anhydrase estradiol analog, in breast cancer cells. PLoS ONE 2013, 8:1.
- [30]Gupta SC, Hevia D, Patchva S, Park B, Koh W, Aggarwal BB: Upsides and downsides of reactive oxygen species for cancer: the roles of reactive oxygen species in tumorigenesis, prevention, and therapy. Antioxid Redox Signal 2012, 16:1295-1322.
- [31]Stander BA, Joubert F, Tu C, Sippel KH, McKenna R, Joubert AM: In vitro evaluation of ESE-15-ol, an estradiol analogue with nanomolar antimitotic and carbonic anhydrase inhibitory activity. PLoS ONE 2012, 7(Suppl 12):e52205.
- [32]Theron AE, Nolte EM, Lafanechere L, Joubert AM: Molecular crosstalk between apoptosis and autophagy indiced by a novel 2-methoxyestradiol analogue in cervical adenocarcinoma cells. Cancer Cell Int 2013, 13:87. BioMed Central Full Text
- [33]Nkandeu DS, Mqoco TV, Visagie MH, Stander BA, Wolmarans E, Cronje MJ, Joubert AM: In vitro changes in mitochondrial potential, aggresome formation and caspase activity by a novel 17-beta-estradiol analogue in breast adenocarcinoma cells. Cell Biochem Funct 2013, 31(Suppl 7):566-574.
- [34]Pretorius E: The role of platelet and fibrin ultrastructure in identifying disease patterns. Pathophysiol Haemost Thromb 2007, 36:251-258.
- [35]Goldstein J, Newbury DE, Joy DC, Lyman CE, Echlin P, Lifshin E, Sawyer L, Micheal JR: Scanning Electron Microscopy and X-ray Microanalysis. 3rd edition. New York: Kluwer Academic/Plenum Publishers; 2002.
- [36]Frank J: Electron Tomography: Three-Dimensional Imaging with the Transmission Electron Microscope. New York: Plenum Press; 1992.
- [37]Brown M, Wittwer C: Flow cytometry: principles and clinical applications in hematology. Clin Chem 2000, 46(Suppl 8B):1221-1229.