Abstract
BackgroundWell-known anti-malarial drug artemisinin exhibits potent anti-cancerous activities. In-vivo and in-vitro studies showed its anti-tumor and immunomodulatory properties signifying it as a potent drug candidate for study. The studies of mechanisms of cell movement are relevant which can be understood by knowing the involvement of genes in an effect of a drug. Although cytotoxicity and anti-proliferative activity of artemisinin is evident, the genes participating in its anti-migratory and reduced invasive effect are not well studied. The present study reports the alteration in the expression of 84 genes involved in cell motility upon artemisinin treatment in MCF-7 breast cancer cells using pathway focused gene expression PCR array. In addition, the effect of artemisinin on epigenetic modifier HDACs is studied.MethodsWe checked the functional stimulus of artemisinin on cell viability, migration, invasion and apoptosis in breast cancerous cell lines. Using qRT-PCR and western blot, we validated the altered expression of relevant genes associated with proliferation, migration, invasion, apoptosis and mammary gland development.ResultsArtemisinin inhibited cell proliferation of estrogen receptor negative breast cancer cells with fewer efficacies in comparison to estrogen receptor positive ones. At the same time, cell viability and proliferation of normal breast epithelial MCF10A cells was un-affected. Artemisinin strongly inhibited cancer cell migration and invasion. Along with orphan nuclear receptors (ERRα, ERRβ and ERRγ), artemisinin altered the ERα/ERβ/PR/Her expression status of MCF-7 cells. The expression of genes involved in the signaling pathways associated with proliferation, migration, invasion and apoptosis was significantly altered which cooperatively resulted into reduced growth promoting activities of breast cancer cells. Interestingly, artemisinin exhibited inhibitory effect on histone deacetylases (HDACs).ConclusionsUpregulated expression of tumor suppressor genes along with reduced expression of oncogenes significantly associated with growth stimulating signaling pathways in response to artemisinin treatment suggests its efficacy as an effective drug in breast cancer treatment.
Highlights
Well-known anti-malarial drug artemisinin exhibits potent anti-cancerous activities
Our results demonstrate the molecular basis of anti-proliferative, migratory, invasion and apoptosis inducing effect of artemisinin in breast cancer
Reduced cell growth and colony formation of breast cancer cells upon artemisinin treatment Cell viability assay performed using MTT suggested that during the initial stage of artemisinin treatment (12 h) there is no significant reduction in viability of the cells but after 24 h of artemisinin treatment the viability of both MCF-7 and T47D breast cancer cells was inhibited in a dose dependent manner (Fig. 1A)
Summary
Well-known anti-malarial drug artemisinin exhibits potent anti-cancerous activities. The studies of mechanisms of cell movement are relevant which can be understood by knowing the involvement of genes in an effect of a drug. Cytotoxicity and anti-proliferative activity of artemisinin is evident, the genes participating in its anti-migratory and reduced invasive effect are not well studied. Genetic and hormone oestrogen are the most important risk factors for breast cancer, factors like high iron content significantly contribute towards tumorigenesis [1,2,3,4,5,6]. Increased and decreased iron content in post and premenopausal women has been explored to be associated with increased breast cancer risk through pathways like oxidative stress and angiogenesis respectively.
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