Computer-based Technology As An Anticancer Agent In Cervical Cancer Cells

A major stumbling block in the fight against cancer remains the identification of novel anticancer compounds that possess cell death-inducing properties in cancer cells leaving non-cancer cells unaffected. Furthermore, researchers now have access to computer software tools including computational simulations for molecular- and cellular modeling. Scientists are now using drug discovery software to identify anticancer compounds based on 3D models of receptors and proteins these compounds bind to. These computational approaches for designing and identifying compounds based on structure-activity relationships are referred to as in silico approaches. These promising compounds can then be synthesized by chemists and scientists so that it can be evaluated in laboratory experiments.

A metabolite of 17β-estradiol naturally found in the body, 2-methoxyestradiol, showed tremendous potential as an anticancer compound by inducing cell death (apoptosis) in cancer cell lines, in rodent trials, and in human trials. However, 2-methoxyestradiol is broken down too quickly by the body. Thus, only small amounts of 2-methoxyestradiol are available to enter the bloodstream and exert anticancer activity in the body. This resulted in the in silico-design of several new compounds based on the modification of the 2-methoxyestradiol structure with additional ethyl- and sulfate groups to effectively induce cell death in cancer cells at reduced concentrations.

This was accomplished by making 3D simulations of how the in silico-designed compounds bind to the target proteins (carbonic anhydrase and tubulin). A study published by Visagie, et al (2016) published in Biological Research evaluated if an in silico-designed compound, 2-ethyl-3-O-sulphamoyl-estra-1,3,5(10),1 5-tetraen-17-ol (ESE-15-ol) (180 nM) is as effective in killing cancer cells as its design intended compared to the parent molecule, 2-methoxyestradiol (1 ÂľM) in cervical cancer cells. Studies indicated that ESE-15-ol does indeed induce apoptosis and dysfunction in the cell cycle progression which is responsible for cell division. Moreover, the study found that ESE-15-ol exposure resulted in cell cycle abnormalities and apoptosis induction at a considerable lower concentration compared to cells exposed to the original compound, 2-methoxyestradiol.

Research published in Cell & Biosciences (2015) and in PlosOne (2013) demonstrated that these in silico-designed sulphamoylated estradiol derivatives induce apoptosis just like the parent compound, 2-methoxyestradiol. In a subsequent study published in PlosOne (2017), we reported that a sulphamoylated compound, 2-ethyl-13-methyl-7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopenta[a]phenanthrane-3,17-diyl bis(sulphamate) (EMBS) decreased cancer proliferation, induced biphasic reactive oxygen species (ROS) production, damaged the DNA and resulted in a aberrational cell division process resulting in apoptosis.

Furthermore, this study demonstrated that ROS and c-Jun N-terminal kinase (JNK)-signalling are essential for EMBS-signalling in breast cancer cell lines. We are currently identifying the specific ROS required for the cell death signaling exerted by the sulphamoylated estradiol compounds in various tumourigenic cell lines. Secondly, the upstream mode of action used by the sulphamoylated estradiol compounds leading to ROS production will be explored as well as subsequent downstream targets resulting in apoptosis induction. This will contribute to what scientists and clinicians know regarding the oxidative-stress dependent signaling used by compounds that cause cell cycle abnormalities in cancer cells.

In conclusion, structure-activity relationship software was successfully used to design compounds that destroy cancer cells and induce apoptosis in several cancer cell lines. Furthermore, lower concentrations could be used to induce equivalent effects or even superior effects when compared to the parent molecule. Subsequent studies have found that these compounds destroy cancer cells utilizing a mode of action that is completely dependent on the generation of ROS and oxidative stress. This suggests a novel oxidative stress-dependent mode of action for in silico-designed sulphamoylated derivatives that cause cell cycle abnormalities.

These findings are described in the article entitled In vitro assessment of a computer-designed potential anticancer agent in cervical cancer cells, published in the journal Biological Research. This work was led by Michelle Visagie from the Faculty of Health Sciences, University of Pretoria.


  • Visagie MH, Jaiswal SR, Joubert AM. In vitro assessment of a computer-designed potential anticancer agent in cervical cancer cells. Biological Research 2016; 49(43).
  • Visagie MH, van den Bout I, Joubert AM. A bis-sulphamoylated estradiol derivative induces ROS-dependent cell cycle abnormalities and subsequent apoptosis. Plos One 2017; 12(4): e0176006.
  • Visagie MH, Birkholtz LM, Joubert AM. A 2-methoxyestradiol bis-sulphamoylated derivative induces apoptosis in breast cell lines. Cell & Biosciences 2015: 5(19).
  • Visagie M, Theron A, Mqoco T, Vieira W, Prudent R, Martinez A, Lafanechère L, Joubert A. Sulphamoylated 2-methoxyestradiol analogues induce apoptosis in adenocarcinoma cells. Plos One 2013: 5(9): e71935.

About The Author

Michelle Visagie

Michelle is a research scientist at the University of Pretoria.

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