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Trans,trans,trans-[PtIV(N3)2(OH)2(py)(NH3)]: a light activated antitumor platinum complex that kills human cancer cells by an apoptosis independent mechanism.
MedLine Citation:
PMID:  22710878     Owner:  NLM     Status:  Publisher    
Abstract/OtherAbstract:
Photoactivatable PtIV diazido complexes have unusual photobiological properties. We demonstrate here that trans,trans,trans-[PtIV(N3)2(OH)2(py)(NH3)] 3 is a potent photoactivated cytotoxin towards human cancer cells in culture, with an average IC50 value in 13 cell lines of 55 ± 28 µM after 30 min (0.12 mW/cm2) photoactivation with UVA light, although visible light was also effective. Photoactivated 3 was non-cross-resistant to cisplatin in 3 of 4 resistant cell lines. Cell swelling but very little blebbing was seen for HL60 cells treated with irradiated 3. Unlike cisplatin and etoposide, both of which cause apoptosis in HL60 cells, no apoptosis was observed for UVA-activated 3 by the Annexin V/propidium iodide flow cytotometry assay. Changes in the levels of the autophagic proteins LC3B-II and p62 in HL60 cells treated with UVA-activated 3 indicate that autophagy is active during cell death. In a clonogenic assay with the SISO human cervix cancer cell line, 3 inhibited colony formation when activated by UVA irradiation. Antitumor activity of 3 in mice bearing xenografted OE19 esophageal carcinoma tumors was photoaugmented by visible light. Insights into the novel reaction pathways of 3 have been obtained from 14N{1H} NMR studies, which show that photoactivation pathways can involve release of free azide in buffered solution. Density functional theory (DFT) and time-dependent DFT (TDDFT) calculations revealed the dissociative character of singlet and triplet excited states of 3, which give rises to reactive, possibly cytotoxic azidyl radicals.
Authors:
Aron F Westendorf; Julie A Woods; Katharina Korpis; Nicola J Farrer; Luca Salassa; Kim Robinson; Virginia Appleyard; Karen Murray; Renate Grünert; Alastair M Thompson; Peter J Sadler; Patrick J Bednarski
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Publication Detail:
Type:  JOURNAL ARTICLE     Date:  2012-6-18
Journal Detail:
Title:  Molecular cancer therapeutics     Volume:  -     ISSN:  1538-8514     ISO Abbreviation:  -     Publication Date:  2012 Jun 
Date Detail:
Created Date:  2012-6-19     Completed Date:  -     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  101132535     Medline TA:  Mol Cancer Ther     Country:  -    
Other Details:
Languages:  ENG     Pagination:  -     Citation Subset:  -    
Affiliation:
1Department of Pharmaceutical and Medicinal Chemistry, Institute of Pharmacy, University of Greifswald.
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