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Slingerland M.,Leiden University | Cerella C.,Laboratory of Molecular and Cellular Biology of Cancer LBMCC | Guchelaar H.J.,Leiden University | Diederich M.,Seoul National University | Gelderblom H.,Leiden University
Investigational New Drugs

Summary: Cardiac glycosides have a long history in the treatment of cardiac disease. However, several preclinical studies as well as two phase I studies have shown that cardenolides may also possess anticancer effects. The mechanisms of these anticancer effects may include intracellular decrease of K+ and increase of Na+ and Ca2+; intracellular acidification; inhibition of IL-8 production and of the TNF-α/NF-κB pathway; inhibition of DNA topoisomerase II and activation of the Src kinase pathway. To date three cardiac glycosides have been developed for treatment of cancer and were tested in a phase 1 clinical trial to determine dose limiting toxicities and maximum tolerated dose. Future studies of this novel class of anticancer drugs are warranted to determine their possible role in cancer treatment. © 2013 Springer Science+Business Media New York. Source

Teiten M.-H.,Laboratory of Molecular and Cellular Biology of Cancer LBMCC | Dicato M.,Laboratory of Molecular and Cellular Biology of Cancer LBMCC | Diederich M.,Seoul National University

Cancer is a multifactorial disease that requires treatments able to target multiple intracellular components and signaling pathways. The natural compound, curcumin, was already described as a promising anticancer agent due to its multipotent properties and huge amount of molecular targets in vitro. Its translation to the clinic is, however, limited by its reduced solubility and bioavailability in patients. In order to overcome these pharmacokinetic deficits of curcumin, several strategies, such as the design of synthetic analogs, the combination with specific adjuvants or nano-formulations, have been developed. By taking into account the risk-benefit profile of drug combinations, as well as the knowledge about curcumin's structure-activity relationship, a new concept for the combination of curcumin with scaffolds from different natural products or components has emerged. The concept of a hybrid curcumin molecule is based on the incorporation or combination of curcumin with specific antibodies, adjuvants or other natural products already used or not in conventional chemotherapy, in one single molecule. The high diversity of such conjugations enhances the selectivity and inherent biological activities and properties, as well as the efficacy of the parental compound, with particular emphasis on improving the efficacy of curcumin for future clinical treatments. © 2014 by the authors. Source

Sawadogo W.R.,Laboratory of Molecular and Cellular Biology of Cancer LBMCC | Sawadogo W.R.,Institute of Health science Research IRSS | Schumacher M.,Laboratory of Molecular and Cellular Biology of Cancer LBMCC | Teiten M.-H.,Laboratory of Molecular and Cellular Biology of Cancer LBMCC | And 3 more authors.

Cancer continues to be a major public health problem despite the efforts that have been made in the search for novel drugs and treatments. The current sources sought for the discovery of new molecules are plants, animals and minerals. During the past decade, the search for anticancer agents of marine origin to fight chemo-resistance has increased greatly. Each year, several novel anticancer molecules are isolated from marine organisms and represent a renewed hope for cancer therapy. The study of structurefunction relationships has allowed synthesis of analogues with increased efficacy and less toxicity. In this report, we aim to review 42 compounds of marine origin and their derivatives that were published in 2011 as promising anticancer compounds. © 2013 by the authors. Source

Ronsberg D.,Heinrich Heine University Dusseldorf | Debbab A.,Heinrich Heine University Dusseldorf | Mandi A.,Debrecen University | Vasylyeva V.,Heinrich Heine University Dusseldorf | And 15 more authors.
Journal of Organic Chemistry

Four tetrahydroxanthone dimers (1-4) and four biogenetically related monomers (5-8), including the new derivatives 4-6, were isolated from the endophyte Phomopsis longicolla. The absolute configurations of 2-4 were established for the first time by TDDFT electronic circular dichroism calculations, and that of phomoxanthone A (1) was revised by X-ray crystallography. Phomoxanthone A (1) showed the strongest pro-apoptotic activity when tested against a panel of human cancer cell lines, including cisplatin-resistant cells, whereas it was up to 100-fold less active against healthy blood cells. It was also the most potent activator of murine T lymphocytes, NK cells, and macrophages, suggesting an activation of the immune system in parallel to its pro-apoptotic activity. This dual effect in combating cancer cells could help in fighting resistance during chemotherapy. Preliminary structure-activity studies of isolated compounds and derivatives obtained by semisynthesis (9a-11) hinted at the location of the biaryl axis and the presence of acetyl groups as important structural elements for the biological activity of the studied tetrahydroxanthones. © 2013 American Chemical Society. Source

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