Induction of apoptosis and inhibition of cell migration and tube-like formation by dihydroartemisinin in murine lymphatic endothelial cells.
ABSTRACT Dihydroartemisinin (DHA) is a semisynthesized agent from the artemisinin first extracted from the Chinese plant Artemisia annua. Previous studies have shown that artemisinin derivates, apart from their antimalarial activity, possess antitumor, antiangiogenic, and anti-inflammatory effects. In the present investigation, DHA was found to have a potent ability in influencing lymphatic endothelial cells (LECs) behavior. Murine LECs were isolated from benign lymphangiomas induced by intraperitoneal injection of incomplete Freund's adjuvant and identified by indirect immunofluorescence assay and fluorescence-activated cell sorting analysis to examine the expression of the specific marker VEGFR-3/Flt-4. When LECs were treated with DHA at 10 microg/ml, the growth of LECs was inhibited, and LECs showed typical apoptotic morphological features, with a higher apoptotic rate as compared with the controls. DHA also exerted a significant inhibitory effect on migration and tube-like formation of LECs in a dose-dependent manner. Quantitative RT-PCR further showed that DHA remarkably downregulated the expression of antiapoptotic bcl-2 mRNA, but upregulated that of the proapoptotic gene bax mRNA. In addition, DHA could strongly attenuate the mRNA and protein levels of VEGFR-3/Flt-4. In summary, these findings indicate that DHA may be useful as a potential lymphangiogenesis inhibitor under induction of cell apoptosis, inhibition of the migration, and formation of tube-like structures in LECs.
- SourceAvailable from: Annalakshmi Chatterjee[Show abstract] [Hide abstract]
ABSTRACT: The antimalarial drug artemisinin from Artemisia annua demonstrated remarkably strong activity against Helicobacter pylori, the pathogen responsible for peptic ulcer diseases. In an effort to develop a novel antimicrobial chemotherapeutic agent containing such a sesquiterpene lactone endoperoxide, a series of analogues (2 natural and 15 semisynthetic molecules), including eight newly synthesized compounds, were investigated against clinical and standard strains of H. pylori. The antimicrobial spectrum against 10 H. pylori strains and a few other bacterial and fungal strains indicated specificity against the ulcer causing organism. Of five promising molecules, a newly synthesized ether derivative β-artecyclopropylmether was found to be the most potent compound, which exhibited MIC range, MIC(90), and minimum bactericidal concentration range values of 0.25 to 1.0 μg/ml, 1.0 μg/ml, and 1 to 16 μg/ml, respectively, against both resistant and sensitive strains of H. pylori. The molecule demonstrated strong bactericidal kinetics with extensive morphological degeneration, retained functional efficacy at stomach acidic pH unlike clarithromycin, did not elicit drug resistance unlike metronidazole, and imparted sensitivity to resistant strains. It is not cytotoxic and exhibits in vivo potentiality to reduce the H. pylori burden in a chronic infection model. Thus, β-artecyclopropylmether could be a lead candidate for anti-H. pylori therapeutics. Since the recurrence of gastroduodenal ulcers is believed to be mainly due to antibiotic resistance of the commensal organism H. pylori, development of a candidate drug from this finding is warranted.09/2012;
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ABSTRACT: We have tested five distinct classes of established and experimental antimalarial drugs for their anticancer potential, using a panel of 91 human cancer lines. Three classes of drugs: artemisinins, synthetic peroxides and DHFR (dihydrofolate reductase) inhibitors effected potent inhibition of proliferation with IC50s in the nM- low µM range, whereas a DHODH (dihydroorotate dehydrogenase) and a putative kinase inhibitor displayed no activity. Furthermore, significant synergies were identified with erlotinib, imatinib, cisplatin, dasatinib and vincristine. Cluster analysis of the antimalarials based on their differential inhibition of the various cancer lines clearly segregated the synthetic peroxides OZ277 and OZ439 from the artemisinin cluster that included artesunate, dihydroartemisinin and artemisone, and from the DHFR inhibitors pyrimethamine and P218 (a parasite DHFR inhibitor), emphasizing their shared mode of action. In order to further understand the basis of the selectivity of these compounds against different cancers, microarray-based gene expression data for 85 of the used cell lines were generated. For each compound, distinct sets of genes were identified whose expression significantly correlated with compound sensitivity. Several of the antimalarials tested in this study have well-established and excellent safety profiles with a plasma exposure, when conservatively used in malaria, that is well above the IC50s that we identified in this study. Given their unique mode of action and potential for unique synergies with established anticancer drugs, our results provide a strong basis to further explore the potential application of these compounds in cancer in pre-clinical or and clinical settings.PLoS ONE 01/2013; 8(12):e82962. · 3.53 Impact Factor
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ABSTRACT: Artemisinin contains an endoperoxide moiety that can react with iron to form cytotoxic free radicals. Cancer cells contain significantly more intracellular free iron than normal cells and it has been shown that artemisinin and its analogs selectively cause apoptosis in many cancer cell lines. In addition, artemisinin compounds have been shown to have anti-angiogenic, anti-inflammatory, anti-metastasis, and growth inhibition effects. These properties make artemisinin compounds attractive cancer chemotherapeutic drug candidates. However, simple artemisinin analogs are less potent than traditional cancer chemotherapeutic agents and have short plasma half-lives, and would require high dosage and frequent administration to be effective for cancer treatment. More potent and target-selective artemisinin-compounds are being developed. These include artemisinin dimers and trimers, artemisinin hybrid compounds, and tagging of artemisinin compounds to molecules that are involved in the intracellular iron-delivery mechanism. These compounds are promising potent anticancer compounds that produce significantly less side effect than traditional chemotherapeutic agents.Investigational New Drugs 08/2012; · 3.50 Impact Factor