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Artemisinin is a drug, widely used in malaria treatment. As the binding affinity of artemisinin and its derivatives dihydroartemisinin and artesunate to blood serum proteins might influence the effectiveness of the drug, binding of artemisinin and derivatives to serum albumin was studied under near physiological conditions. Binding kinetics indicate a simple, single-step association process for all artemisinin derivatives. The determined changes in enthalpy and entropy upon drug binding clearly indicate that hydrophobic forces are most important for artemisinin and dihydroartemisinin binding, whereas binding of artesunate is governed by both hydrophilic and hydrophobic forces. Key residues, which are most likely involved in binding of the respective compounds, were identified in subsequent protein/drug docking studies. The obtained results not only explain differences in between artemisinin and derivatives but generally illustrate how slight modifications in a drug can significantly affect principles underlying drug binding to target proteins.

Malaria causes millions of death cases per year. Since Plasmodium falciparum rapidly develops drug resistance, it is of high importance to investigate potential drug targets which may lead to novel rational therapy approaches. Here we report on the interaction of translationally controlled tumor protein of P. falciparum (PfTCTP) with the anti-malarial drug artemisinin. Furthermore, we investigated the crystal structure of PfTCTP. Using mass spectrometry, bioinformatic approaches and surface plasmon resonance spectroscopy, we identified novel binding sites of artemisinin which are in direct neighborhood to amino acids 19-46, 108-134 and 140-163. The regions covered by these residues are known to be functionally important for TCTP function. We conclude that interaction of artemisinin with TCTP may be at least in part explain the antimalarial activity of artemisinin.

Curcuma longa L. has long been used as a medicinal plant in traditional Chinese medicine against abdominal disorders. Its active constituent curcumin has anti-inflammatory, chemopreventive and cytotoxic properties. In the present investigation, we have analyzed the cytotoxic activity of curcumin and four derivatives. Among these compounds, ethoxycurcumintrithiadiazolaminomethylcarbonate was the most cytotoxic one. The curcumin-type compounds were not cross-resistant to standard anticancer drugs and were not involved in ATP-binding cassette transporter-mediated multidrug resistance. A combined approach of messenger RNA-based microarray profiling, COMPARE analyses and signaling pathway analyses identified genes as determinants of sensitivity and resistance to curcumin and specific signaling routes involved in cellular response to curcumin. These genes may be useful as biomarkers to develop individualized treatment options in the future. From a nutritional point of view, it is a thriving perspective to further investigate whether C. longa may be used as a spice to improve cancer therapy.

Determining cellular target molecules of drugs by chemical proteomic techniques is complex and tedious. Most approaches rely on activity-based probe profiling and compound-centric chemical proteomics. The antimalarial artemisinin also exerts profound anti-cancer activity, but the mechanisms of action are incompletely understood. In the present study, we have identified artemisinin-interacting target proteins from human nasopharyngeal carcinoma cell line CNE1. Thereby, our approach overcomes usual problems in traditional fishing procedures, because the drug was attached to a polystyrene surface without further chemical modification. Using mass spectrometry we have identified 20 proteins which effect cell cycle arrest, apoptosis, inhibition of angiogenesis, disruption of cell migration, and modulation of nuclear receptor responsiveness. One protein out of the twenty was further investigated in vitro for direct ligand binding. Furthermore, a blind-docking based approach confirmed experimentally identified proteins and suggested further interacting proteins. Theoretically predicted interaction partners may serve as a starting point to complete the whole set of proteins binding artemisinin. In our investigations, we have comprised artemisinins role in cancer treatment in a greater shape through a systematic biological strategy and thus, are able to show novel insights into its mode of action. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1993. doi:1538-7445.AM2012-1993

The Gwich’in, which belong to the Athapaskan language group of Native Americans live in the borderland between Alaska and Canada. We analyzed 29 medicinal plants of this tribe for their growth inhibitory activity against CCRF-CEM T-cell acute lymphoblastic leukemia (T-ALL) cells. The anti-leukemic activity of these plants has not been investigated as yet. Considering the poor cure rates of some ALL forms, there might be a great potential for medicinal plants as resource for natural products to treat T-ALL. We found that the hexane extracts of three plants revealed considerable growth inhibition on CCRF-CEM cells. The 50% inhibition concentrations (IC50) were 6.63 ± 0.03 µg/ml for Cladina mitis, 8.65 ± 0.38 µg/ml for Picea mariana (needles), and 9.67 ± 1.36 µg/ml for Artemisia frigida. Further investigations are required to isolate the active constituents of these plants.

Background Malignant diseases are responsible of approximately 13% of all deaths each year in the world. Natural products represent a valuable source for the development of novel anticancer drugs. The present study was aimed at evaluating the cytotoxicity of a naphtyl butanone isolated from the leaves of Guiera senegalensis, guieranone A (GA). Results The results indicated that GA was active on 91.67% of the 12 tested cancer cell lines, the IC50 values below 4 μg/ml being recorded on 83.33% of them. In addition, the IC50 values obtained on human lymphoblastic leukemia CCRF-CEM (0.73 μg/ml) and its resistant subline CEM/ADR5000 (1.01 μg/ml) and on lung adenocarcinoma A549 (0.72 μg/ml) cell lines were closer or lower than that of doxorubicin. Interestingly, low cytotoxicity to normal hepatocyte, AML12 cell line was observed. GA showed anti-angiogenic activity with up to 51.9% inhibition of the growth of blood capillaries on the chorioallantoic membrane of quail embryo. Its also induced apotosis and cell cycle arrest. Ingenuity Pathway Analysis identified several pathways in CCRF-CEM cells and functional group of genes regulated upon GA treatment (P < 0.05), the Cell Cycle: G2/M DNA Damage Checkpoint Regulation and ATM Signaling pathways being amongst the four most involved functional groups. Conclusion The overall results of this work provide evidence of the cytotoxic potential of GA and supportive data for its possible use in cancer chemotherapy.