Novel in silico-designed estradiol analogues are cytotoxic to a multidrug-resistant cell line at nanomolar concentrations
Theron, A.E. (Anne Elisabeth); Prudent, Renaud; Nolte, Elsie M.; Van den Bout, Jan Iman; Punchoo, Rivak; Marais, Sumari; Du Toit, Peet J.; Hlophe, Yvette; Van Papendorp, D.H. (Dirk Hermanus), 1949-; Lafanechere, Laurence; Joubert, Annie M.
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
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.