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      Synergistic Inhibition of Angiogenesis by Artesunate and Captopril In Vitro and In Vivo

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          Abstract

          Inhibition of angiogenesis represents one major strategy of cancer chemotherapy. In the present investigation, we investigated the synergism of artesunate and captopril to inhibit angiogenesis. Artesunate is an antimalarial derivative of artemisinin from the Chinese medicinal plant, Artemisia annua L., which also reveals profound anticancer activity in vitro and in vivo. Captopril is an angiotensin I-converting (ACE) inhibitor, which is well established in Western academic medicine. Both compounds inhibited migration of human umbilical vein endothelial cells (HUVECs) in vitro. The combination of both drugs resulted in synergistically inhibited migration. Whereas artesunate inhibited HUVEC growth in the XTT assay, captopril did not, indicating independent modes of action. We established a chorioallantoic membrane (CAM) assay of quail embryos ( Coturnix coturnix L.) and a computer-based evaluation routine for quantitative studies on vascularization processes in vivo. Artesunate and captopril inhibited blood vessel formation and growth. For the first time, we demonstrated that both drugs revealed synergistic effects when combined. These results may also have clinical impact, since cardiovascular diseases and cancer frequently occur together in older cancer patients. Therefore, comorbid patients may take advantage, if they take captopril to treat cardiovascular symptoms and artesunate to treat cancer.

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          Qinghaosu (artemisinin): an antimalarial drug from China.

          The herb Artemisia annua has been used for many centuries in Chinese traditional medicine as a treatment for fever and malaria. In 1971, Chinese chemists isolated from the leafy portions of the plant the substance responsible for its reputed medicinal action. This compound, called qinghaosu (QHS, artemisinin), is a sesquiterpene lactone that bears a peroxide grouping and, unlike most other antimalarials, lacks a nitrogen-containing heterocyclic ring system. The compound has been used successfully in several thousand malaria patients in China, including those with both chloroquine-sensitive and chloroquine-resistant strains of Plasmodium falciparum. Derivatives of QHS, such as dihydroqinghaosu, artemether, and the water-soluble sodium artesunate, appear to be more potent than QHS itself. Sodium artesunate acts rapidly in restoring to consciousness comatose patients with cerebral malaria. Thus QHS and its derivatives offer promise as a totally new class of antimalarials.
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            Artemisinins target the SERCA of Plasmodium falciparum.

            Artemisinins are extracted from sweet wormwood (Artemisia annua) and are the most potent antimalarials available, rapidly killing all asexual stages of Plasmodium falciparum. Artemisinins are sesquiterpene lactones widely used to treat multidrug-resistant malaria, a disease that annually claims 1 million lives. Despite extensive clinical and laboratory experience their molecular target is not yet identified. Activated artemisinins form adducts with a variety of biological macromolecules, including haem, translationally controlled tumour protein (TCTP) and other higher-molecular-weight proteins. Here we show that artemisinins, but not quinine or chloroquine, inhibit the SERCA orthologue (PfATP6) of Plasmodium falciparum in Xenopus oocytes with similar potency to thapsigargin (another sesquiterpene lactone and highly specific SERCA inhibitor). As predicted, thapsigargin also antagonizes the parasiticidal activity of artemisinin. Desoxyartemisinin lacks an endoperoxide bridge and is ineffective both as an inhibitor of PfATP6 and as an antimalarial. Chelation of iron by desferrioxamine abrogates the antiparasitic activity of artemisinins and correspondingly attenuates inhibition of PfATP6. Imaging of parasites with BODIPY-thapsigargin labels the cytosolic compartment and is competed by artemisinin. Fluorescent artemisinin labels parasites similarly and irreversibly in an Fe2+-dependent manner. These data provide compelling evidence that artemisinins act by inhibiting PfATP6 outside the food vacuole after activation by iron.
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              From traditional Chinese medicine to rational cancer therapy.

              Many natural products and derivatives thereof belong to the standard repertoire of cancer chemotherapy. Examples are Vinca alkaloids, taxanes and camptothecins. In recent years, the potential of natural products from plants, notably from medicinal plants used in traditional Chinese medicine (TCM), has been recognized by the scientific community in the Western world. To provide an example of the most recent developments in this field, we have selected several compounds, namely artesunate, homoharringtonine, arsenic trioxide and cantharidin, that are found in natural TCM products and that have the potential for use in cancer therapy. Controlled clinical studies have shown that homoharringtonine and arsenic trioxide can exert profound activity against leukaemia. Increased knowledge of the molecular mechanisms of TCM-derived drugs and recent developments in their applications demonstrate that the combination of TCM with modern cutting-edge technologies provides an attractive strategy for the development of novel and improved cancer therapeutics.
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                Author and article information

                Journal
                Evid Based Complement Alternat Med
                Evid Based Complement Alternat Med
                ECAM
                Evidence-based Complementary and Alternative Medicine : eCAM
                Hindawi Publishing Corporation
                1741-427X
                1741-4288
                2013
                8 October 2013
                8 October 2013
                : 2013
                : 454783
                Affiliations
                Department of Pharmaceutical Biology, Institute of Pharmacy and Biochemistry, Johannes Gutenberg University, Staudinger Weg 5, 55128 Mainz, Germany
                Author notes

                Academic Editor: Shrikant Anant

                Article
                10.1155/2013/454783
                3816047
                29e25729-29fd-4751-8dc6-5c8016f0d621
                Copyright © 2013 Benjamin Krusche et al.

                This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

                History
                : 6 June 2013
                : 15 August 2013
                : 20 August 2013
                Categories
                Research Article

                Complementary & Alternative medicine
                Complementary & Alternative medicine

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