Antimitotic drugs in the treatment of cancer

Cancer is a complex disease since it is adaptive in such a way that it can promote proliferation and invasion by means of an overactive cell cycle and in turn cellular division which is targeted by antimitotic drugs that are highly validated chemotherapy agents. However, antimitotic drug cytotoxicity to non-tumorigenic cells and multiple cancer resistance developed in response to drugs such as taxanes and vinca alkaloids are obstacles faced in both the clinical and basic research field to date. In this review, the classes of antimitotic compounds, their mechanisms of action and cancer cell resistance to chemotherapy and other limitations of current antimitotic compounds are highlighted, as well as the potential of novel 17-β estradiol analogs as cancer treatment.Medical Research Council of South Africa, the Research Committee of the Faculty of Health Sciences of the University of Pretoria, the Cancer association of South Africa and the National Research Foundation.http://link.springer.com/journal/280hb201

<i>In vitro<i/> influence of 2-methoxyestradiol-bis-sulphamate on cell numbers, reactive oxygen species production and autophagy induction in a breast adenocarcinoma- and a non- tumorigenic breast epithelial cell line.

<div style="font-size: 12px; font-family: serif; left: 487.183px; top: 485.04px; transform: scale(1.10189, 1); transform-origin: 0% 0% 0px;" dir="ltr">Die doel van die studie was om die in vitro effekte van 2-metoksiëstradiol-bis-sulfamaat</div><div style="font-size: 12px; font-family: serif; left: 227.349px; top: 501.04px; transform: scale(1.0899, 1); transform-origin: 0% 0% 0px;" dir="ltr">op sellgroei, morfologie, reaktiewe suurstof spesie generasie en outofagie in ‘n borsepiteel adenokarsinoom (MCF-7) en ‘n nie-kankersellyn (MCF-12A) te ondersoek.</div

Dysregulation of Catalase by a Sulphamoylated Estradiol Analogue Culminates in Antimitotic Activity and Cell Death Induction in Breast Cancer Cell Lines

Recent findings revealed that 2-ethyl-17-oxoestra-1,3,5(10)-trien-3-yl sulfamate (ESE-one) induces antiproliferative activity and cell rounding dependent on the generation of superoxide anion, hydrogen peroxide and peroxyl radical. In the current study, the role of these reactive oxygen species was assessed in the activity exerted by ESE-one on cell cycle progression, mitochondrial membrane potential and cell death induction in breast tumorigenic cells. The influence of ESE-one was also investigated on superoxide dismutase and catalase activity. ESE-one induced a time-dependent accumulation of cells in the G1 phase and G2/M phase that is partially impaired by tiron and trolox and N,N′-dimethylthiourea suggesting that superoxide anion, hydrogen peroxide and peroxyl radical are required for these effects exerted by ESE-one. Flow cytometry data in MCF-7 cells demonstrated that tiron decreased depolarization of the membrane potential in ESE-one exposed cells, indicating that superoxide anion plays a role in the depolarization effects induced by ESE-one. Spectrophotometry data showed that ESE-one decreased catalase activity in both cell lines. This study contributes towards pertinent information regarding the effects of an in silico-designed sulfamoylated compound on antioxidant enzymes leading to aberrant quantities of specific reactive oxygen species resulting in antimitotic activity culminating in the induction of cell death in breast cancer cell lines

Sulphamoylated Estradiol Analogue Induces Reactive Oxygen Species Generation to Exert Its Antiproliferative Activity in Breast Cancer Cell Lines

2-Methoxyestradiol (2ME), a 17&beta;-estradiol metabolite, exerts anticancer properties in vitro and in vivo. To address 2ME&rsquo;s low bioavailability, research led to the in silico design of sulphamoylated 2ME analogues. However, the role of oxidative stress induced in the activity exerted by sulphamoylated compounds remains elusive. In the current study, the influence of 2-Ethyl-17-oxoestra-1,3,5(10)-trien-3-yl sulphamate (ESE-one) on reactive oxygen species (ROS) induction and its effect on cell proliferation, as well as morphology, were assessed in breast tumorigenic cells (MCF-7 and MDA-MB-231). Fluorescent microscopy showed that sulphamoylated estradiol analogues induced hydrogen peroxide and superoxide anion, correlating with decreased cell growth demonstrated by spectrophotometry data. ESE-one exposure resulted in antiproliferation which was repressed by tiron (superoxide inhibitor), trolox (peroxyl inhibitor) and N,N&prime;-dimethylthiourea (DMTU) (hydrogen peroxide inhibitor). Morphological studies demonstrated that tiron, trolox and DMTU significantly decreased the number of rounded cells and shrunken cells in MCF-7 and MDA-MB-231 cells induced by ESE-one. This in vitro study suggests that ESE-one induces growth inhibition and cell rounding by production of superoxide anion, peroxyl radical and hydrogen peroxide. Identification of these biological changes in cancer cells caused by sulphamoylated compounds hugely contributes towards improvement of anticancer strategies and the ROS-dependent cell death pathways in tumorigenic breast cells

Molecular Farming of Pembrolizumab and Nivolumab

Immune checkpoint inhibitors (ICIs) are a class of immunotherapy agents capable of alleviating the immunosuppressive effects exerted by tumorigenic cells. The programmed cell death protein 1 (PD-1)/programmed death-ligand 1 (PD-L1) immune checkpoint is one of the most ubiquitous checkpoints utilized by tumorigenic cells for immune evasion by inducing apoptosis and inhibiting the proliferation and cytokine production of T lymphocytes. Currently, the most frequently used ICIs targeting the PD-1/PD-L1 checkpoint include monoclonal antibodies (mAbs) pembrolizumab and nivolumab that bind to PD-1 on T lymphocytes and inhibit interaction with PD-L1 on tumorigenic cells. However, pembrolizumab and nivolumab are costly, and thus their accessibility is limited in low- and middle-income countries (LMICs). Therefore, it is essential to develop novel biomanufacturing platforms capable of reducing the cost of these two therapies. Molecular farming is one such platform utilizing plants for mAb production, and it has been demonstrated to be a rapid, low-cost, and scalable platform that can be potentially implemented in LMICs to diminish the exorbitant prices, ultimately leading to a significant reduction in cancer-related mortalities within these countries

Dysregulation of Catalase by a Sulphamoylated Estradiol Analogue Culminates in Antimitotic Activity and Cell Death Induction in Breast Cancer Cell Lines

Recent findings revealed that 2-ethyl-17-oxoestra-1,3,5(10)-trien-3-yl sulfamate (ESE-one) induces antiproliferative activity and cell rounding dependent on the generation of superoxide anion, hydrogen peroxide and peroxyl radical. In the current study, the role of these reactive oxygen species was assessed in the activity exerted by ESE-one on cell cycle progression, mitochondrial membrane potential and cell death induction in breast tumorigenic cells. The influence of ESE-one was also investigated on superoxide dismutase and catalase activity. ESE-one induced a time-dependent accumulation of cells in the G1 phase and G2/M phase that is partially impaired by tiron and trolox and N,N&prime;-dimethylthiourea suggesting that superoxide anion, hydrogen peroxide and peroxyl radical are required for these effects exerted by ESE-one. Flow cytometry data in MCF-7 cells demonstrated that tiron decreased depolarization of the membrane potential in ESE-one exposed cells, indicating that superoxide anion plays a role in the depolarization effects induced by ESE-one. Spectrophotometry data showed that ESE-one decreased catalase activity in both cell lines. This study contributes towards pertinent information regarding the effects of an in silico-designed sulfamoylated compound on antioxidant enzymes leading to aberrant quantities of specific reactive oxygen species resulting in antimitotic activity culminating in the induction of cell death in breast cancer cell lines

<i>In vitro</i> veranderinge in mitochondriale membraan potensiaal, aggresoom formasie en kaspase aktiwiteit deur `n nuwe 17-β-estradiol analoog in bors adenokarsinoomselle

<div style="font-size: 12px; font-family: serif; left: 543.465px; top: 340.284px; transform: scale(1.04355, 1); transform-origin: 0% 0% 0px;" dir="ltr">Die natuurlike metaboliet van estradiol, naamlik 2-metoksieëstradiol (2ME2) oefen antiproliferatiewe en anti-tumor effekte in vitro en <em>in vivo</em> uit met minimale of geen toksisiteit nie.</div