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Cellular localization of iron(II) polypyridyl complexes determines their anticancer action mechanisms

Paper ID Volume ID Publish Year Pages File Format Full-Text
5489 392 2015 10 PDF Available
Title
Cellular localization of iron(II) polypyridyl complexes determines their anticancer action mechanisms
Abstract

Elucidation of relationship among cellular uptake, localization and biological activities of metal complexes could make great breakthrough in the understanding of their action mechanisms and provide useful information for rational design of metal-based anticancer drugs. Iron(II) complexes have emerged as potential anticancer drug candidates with application potential in cancer imaging and therapy. Herein, a series of iron(II) polypyridyl complexes with different lipophilicity were rationally designed, synthesized and identified as potent anticancer agents. The relationship between the cellular localization and molecular action mechanisms of the complexes was also elucidated. The results showed that, the increase in planarity of the Fe(II) polypyridyl complexes enhanced their lipophilicity and cellular uptake, leading to improved anticancer efficacy. The hydrophilic Fe(II) complex entered cancer cells through transferring receptor (TfR)-mediated endocytosis, and translocated to cell nucleus, where they induced S phase cell cycle arrest through triggering DNA damage-mediated p53 pathway. Interestingly, the hydrophobic Fe(II) complexes displayed higher anticancer efficacy than the hydrophilic ones, but shared the same uptake pathway (TfR-mediated endocytosis) in cancer cells. They accumulated and localized in cell cytoplasm, and induced G0/G1 cells cycle arrest through regulation of AKT pathway and activation of downstream effector proteins. These results support that the cellular localization of Fe(II) complexes regulated by their lipophilicity could affect the anticancer efficacy and action mechanisms. Taken together, this study may enhance our understanding on the rational design of the next-generation anticancer metal complexes.

Graphical abstractHerein we demonstrate that cellular localization of iron(II) polypyridyl complexes determines their anticancer action mechanisms. Hydrophilic complex located in cell nucleus and resulted in S phase cell cycle arrest, while the more lipophilic complexes remained in cytoplasm and induced G0/G1 phase cell cycle arrest.Figure optionsDownload full-size imageDownload high-quality image (267 K)Download as PowerPoint slide

Keywords
Iron(II) polypyridyl complexes; Cellular localization; Cellular uptake; Action mechanisms
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Cellular localization of iron(II) polypyridyl complexes determines their anticancer action mechanisms
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Publisher
Database: Elsevier - ScienceDirect
Journal: Biomaterials - Volume 71, December 2015, Pages 168–177
Authors
, , , , , ,
Subjects
Physical Sciences and Engineering Chemical Engineering Bioengineering
Get Full-Text Now
Don't Miss Today's Special Offer
Price was $35.95
You save - $31
Price after discount Only $4.95
100% Money Back Guarantee
Full-text PDF Download
Online Support
Any Questions? feel free to contact us