Bioinformatic and experimental fishing for artemisinin-interacting proteins from human nasopharyngeal cancer cells
Department of Pharmaceutical Biology, Institute of Pharmacy and Biochemistry, Johannes Gutenberg University of Mainz, Staudinger Weg 5, 55128 Mainz, Germany. Molecular BioSystems
(Impact Factor: 3.21).
04/2012; 8(4):1311-8. DOI: 10.1039/c2mb05437j
Determining interacting cellular partners of drugs by chemical proteomic techniques is complex and tedious. Most approaches rely on activity-based probe profiling and compound-centric chemical proteomics. The anti-malarial artemisinin also exerts profound anti-cancer activity, but the mechanisms of action are incompletely understood. In the present investigation, we present a novel approach to identify artemisinin-interacting target proteins. Our approach overcomes usual problems in traditional fishing procedures, because the drug was attached to a surface without further chemical modification. The proteins identified effect among others, cell cycle arrest, apoptosis, inhibition of angiogenesis, disruption of cell migration, and modulation of nuclear receptor responsiveness. Furthermore, a bioinformatic approach confirmed experimentally identified proteins and suggested a large number of other interacting proteins. Theoretically predicted interaction partners may serve as a starting point to complete the whole set of proteins binding artemisinin.
Available from: Elmar Breuer
- "leukemia, lymphoma, melanoma, brain tumors, carcinoma of the colon, breast, ovary, lung, kidney, and many others [8–10]. Investigations into the mode of action revealed that artemisinin may form active radical oxygen species and carbon-centered radical molecules leading to oxidative stress [11–15], DNA damage [16, 17], adduct formation of specific target proteins [18, 19], cell cycle arrest , interaction with signal transduction pathways [21–26], induction of apoptosis and autophagy [7, 27–31], and inhibition of angiogenesis [32–35]. Artemisinin-type drugs have also been shown to act against cancer in vivo using transplantable murine syngeneic tumors [6, 36–38] and human xenograft tumors [32, 39–47]. "
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ABSTRACT: Artemisinin, a constituent of Artemisia annua L., is a well-known antimalarial drug. Artemisinin-type drugs also inhibit cancer growth in vitro and in vivo. Herbal extracts of A.
annua inhibit the growth of cancer cell lines. Here, we report on the use of capsules containing powder of Herba Artemisiae annuae to treat pet sarcoma. The surgical tumor removal as standard treatment was supplemented by adjuvant therapy with A.
annua. One cat and one dog with fibrosarcoma survived 40 and 37 months, respectively, without tumor relapse. Two other dogs suffering from fibrosarcoma and hemangioendothelial sarcoma also showed complete remission and are still alive after 39 and 26 months, respectively. A.
annua was well tolerated without noticeable side effects. These four cases indicate that A.
annua may be a promising herbal drug for cancer therapy.
Available from: spandidos-publications.com
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ABSTRACT: Retinoblastoma (RB) is an intraocular cancer that affects young children. There is an ongoing effort to find new agents for RB management that are effective, specific and with few side-effects. In the present study, we tested artesunate (ART), a synthetic derivative from the herbal drug artemisinin, used in the clinic for the treatment of malaria. We analyzed ART cytotoxicity in an RB cell line (RB-Y79) and in a retinal epithelial cell line (hTERT-RPE1) by flow cytometric analysis (FCM). We related the effect of ART to the expression of transferrin receptor 1 (TfR-1, also known as CD71) by knocking down CD71 with RNAi and analyzing cell cycle variables by FCM. We found that the cytotoxic action of ART is specific for RB cells in a dose-dependent manner, with low toxicity in normal retina cells. ART is more effective in RB than carboplatin with a markedly strong cytotoxic effect on carboplatin-resistant RB cells. RB had higher CD71 levels at the membrane compared to normal retinal cells. We showed that ART internalization in RB cells is dependent upon the expression of the CD71. In addition, ART blocked the cell cycle progression at the G1 phase, even at low doses, and decreased the proportion of RB cells in the S phase. In conclusion, we showed that ART is a promising drug exhibiting high selective cytotoxicity even against multidrug-resistant RB cells. Thus, we suggest that ART could be used in the treatment of RB.
Available from: Yongyuth Yuthavong
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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.
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