Novel in silico-designed estradiol analogues are cytotoxic to a multidrug-resistant cell line at nanomolar concentrations

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dc.contributor.author Theron, A.E. (Anne Elisabeth)
dc.contributor.author Prudent, Renaud
dc.contributor.author Nolte, Elsie M.
dc.contributor.author Van den Bout, Jan Iman
dc.contributor.author Punchoo, Rivak
dc.contributor.author Marais, Sumari
dc.contributor.author Du Toit, Peet J.
dc.contributor.author Hlophe, Yvette
dc.contributor.author Van Papendorp, D.H. (Dirk Hermanus), 1949-
dc.contributor.author Lafanechere, Laurence
dc.contributor.author Joubert, Annie M.
dc.date.accessioned 2016-02-10T08:34:44Z
dc.date.issued 2015-02
dc.description.abstract PURPOSE : 2-Methoxyestradiol (2ME) is a promising anticancer agent that disrupts the integrity and dynamics of the spindle network. In order to overcome the pharmacokinetic constraints of this compound, a panel of sulphamoylated estradiol analogues were in silico-designed by our laboratory. In this study, we analysed the potential of each analogue to induce cell death on a panel of cancer cell lines. Moreover, the mechanism of action of the most effective compounds was determined. METHODS : Cytotoxicity screening of the compounds and intermediates was performed on five different cancer cell lines to determine IG50 values. An in vitro tubulin polymerization assay was done to determine the effect of the drugs on tubulin polymerization while their intracellular effects on the microtubule network were assessed by immunofluorescence microscopy. RESULTS : IG50 calculations showed that the sulphamoylated analogues induce cytotoxicity at nanomolar concentrations in all cell lines, including the P-glycoprotein pump overexpressing multidrug-resistant uterine sarcoma cell line. The non-sulphamoylated compounds were only cytotoxic at micromolar ranges, if at all. The sulphamoylated compounds inhibited pure tubulin polymerization in a dose-dependent manner and induced microtubule destruction in cells after 24-h exposure. CONCLUSION : Results revealed that the novel sulphamoylated 2ME derivatives have potential as anti-cancer drugs, possibly even against chemoresistant cancer cells. These compounds disrupt the intracellular microtubule integrity which leads to mitotic block of the cells. en_ZA
dc.description.embargo 2016-02-28
dc.description.librarian hb2015 en_ZA
dc.description.sponsorship The Research Development Programme of the University of Pretoria (RDP AOV840), the South African Medical Association (SAMA), the National Research Foundation (NRF Project # 86475, N00465, N00375, N00591), the Research Committee of the Faculty of Health Sciences, University of Pretoria (RESCOM), CANSA (AOV741, AOW228) and the Medical Research Council (MRC AOW110). en_ZA
dc.description.uri http://link.springer.com/journal/280 en_ZA
dc.identifier.citation Theron, AE, Prudent, R, Nolte, EM, Van den Bout, JI, Punchoo, R, Marais, S, Du Toit, PJ, Hlophe, Y, Van Papendorp, DH, Lafanechere, L & Joubert, AM 2015, 'Novel in silico-designed estradiol analogues are cytotoxic to a multidrug-resistant cell line at nanomolar concentrations', Cancer Chemotherapy and Pharmacology, vol. 75, no. 2, pp. 431-437. en_ZA
dc.identifier.issn 0344-5704 (print)
dc.identifier.issn 1432-0843 (online)
dc.identifier.other 10.1007/s00280-014-2653-z
dc.identifier.uri http://hdl.handle.net/2263/51311
dc.language.iso en en_ZA
dc.publisher Springer en_ZA
dc.rights © Springer-Verlag Berlin Heidelberg 2014. The original publication is available at : http://link.springer.com/journal/280. en_ZA
dc.subject Multidrug resistance en_ZA
dc.subject 2-Methoxyestradiol analogue en_ZA
dc.subject Anti-mitotic en_ZA
dc.subject Cytotoxicity en_ZA
dc.subject Microtubule dynamics en_ZA
dc.subject Tubulin en_ZA
dc.title Novel in silico-designed estradiol analogues are cytotoxic to a multidrug-resistant cell line at nanomolar concentrations en_ZA
dc.type Postprint Article en_ZA


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