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Minor structural modifications to alchemix influence mechanism of action and pharmacological activity
Stockholm University, Faculty of Science, Department of Genetics, Microbiology and Toxicology.
Stockholm University, Faculty of Science, Department of Genetics, Microbiology and Toxicology.
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2012 (English)In: Biochemical Pharmacology, ISSN 0006-2952, E-ISSN 1873-2968, Vol. 83, no 11, 1514-1522 p.Article in journal (Refereed) Published
Abstract [en]

Alchemix is an exemplar of a class of anthraquinone with efficacy against multidrug resistant tumours. We have explored further the mechanism of action of alchemix and investigated the effect of extending its side arm bearing the alkylating functionality with regard to DNA binding and activity against multidrug resistant cancer cells. Increasing the distance between the intercalating chromophore and the alkylating functionality of ICT2901 (propyl), ICT2902 (butyl) and ICT2903 (pentyl), led to a higher number of DNA alkylation sites, more potent topoisomerase II inhibition and generated more apoptotic and necrotic cells when analysed in p53-proficient HCT116 cells. Intriguingly, alchemix, the compound with the shortest distance between its intercalative chromophore and alkylating functionality (ethyl), did not conform to this SAR. A different toxicity pattern against DNA repair defective CHO cell lines as well as arrest of cells in Cl supports a somewhat distinct mode of action by alchemix compared with its analogues. Importantly, both alchemix and ICT2901 demonstrated greater cytotoxic activity against anthraquinone-resistant MCF-7/adr cells than wild-type MCF-7 cells. Subtle synthetic modification in this anthraquinone series has led to significant changes to the stability of DNA-compound complexes and cellular activity. Given that the failure of chemotherapy in the clinic is often associated with MDR, the results of both alchemix and ICT2901 represent important advances towards improved therapies.

Place, publisher, year, edition, pages
2012. Vol. 83, no 11, 1514-1522 p.
Keyword [en]
Anthraquinone, H2AX phosphorylation, MDR, Topoisomerase II, NER, p53
National Category
Pharmacology and Toxicology
URN: urn:nbn:se:su:diva-79770DOI: 10.1016/j.bcp.2012.02.017ISI: 000303078700005OAI: diva2:551873


Available from: 2012-09-12 Created: 2012-09-11 Last updated: 2012-09-12Bibliographically approved

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Helleday, Thomas
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