Novel mechanism of cytotoxicity for the selective selenosemicarbazone, 2-acetylpyridine 4,4-dimethyl-3-selenosemicarbazone (Ap44mSe): lysosomal membrane permeabilization

Al-Eisawi, Zaynab, Stefani, Christian, Jansson, Patric J., Arvind, Akanksha, Sharpe, Philip C., Basha, Maram T., Iskander, George M., Kumar, Naresh, Kovacevic, Zaklina, Lane, Darius J. R., Sahni, Sumit, Bernhardt, Paul V., Richardson, Des R. and Kalinowski, Danuta S. (2016) Novel mechanism of cytotoxicity for the selective selenosemicarbazone, 2-acetylpyridine 4,4-dimethyl-3-selenosemicarbazone (Ap44mSe): lysosomal membrane permeabilization. Journal of Medicinal Chemistry, 59 1: 294-312. doi:10.1021/acs.jmedchem.5b01399


Author Al-Eisawi, Zaynab
Stefani, Christian
Jansson, Patric J.
Arvind, Akanksha
Sharpe, Philip C.
Basha, Maram T.
Iskander, George M.
Kumar, Naresh
Kovacevic, Zaklina
Lane, Darius J. R.
Sahni, Sumit
Bernhardt, Paul V.
Richardson, Des R.
Kalinowski, Danuta S.
Title Novel mechanism of cytotoxicity for the selective selenosemicarbazone, 2-acetylpyridine 4,4-dimethyl-3-selenosemicarbazone (Ap44mSe): lysosomal membrane permeabilization
Journal name Journal of Medicinal Chemistry   Check publisher's open access policy
ISSN 1520-4804
0022-2623
Publication date 2016-01-14
Year available 2015
Sub-type Article (original research)
DOI 10.1021/acs.jmedchem.5b01399
Open Access Status Not Open Access
Volume 59
Issue 1
Start page 294
End page 312
Total pages 19
Place of publication Washington, DC United States
Publisher American Chemical Society
Collection year 2016
Language eng
Abstract Selenosemicarbazones show marked antitumor activity. However, their mechanism of action remains unknown. We examined the medicinal chemistry of the selenosemicarbazone, 2-acetylpyridine 4,4-dimethyl-3-selenosemicarbazone (Ap44mSe), and its iron and copper complexes to elucidate its mechanisms of action. Ap44mSe demonstrated a pronounced improvement in selectivity toward neoplastic relative to normal cells compared to its parent thiosemicarbazone. It also effectively depleted cellular Fe, resulting in transferrin receptor-1 up-regulation, ferritin down-regulation, and increased expression of the potent metastasis suppressor, N-myc downstream regulated gene-1. Significantly, Ap44mSe limited deleterious methemoglobin formation, highlighting its usefulness in overcoming toxicities of clinically relevant thiosemicarbazones. Furthermore, Cu-Ap44mSe mediated intracellular reactive oxygen species generation, which was attenuated by the antioxidant, N-acetyl-l-cysteine, or Cu sequestration. Notably, Ap44mSe forms redox active Cu complexes that target the lysosome to induce lysosomal membrane permeabilization. This investigation highlights novel structure–activity relationships for future chemotherapeutic design and underlines the potential of Ap44mSe as a selective anticancer/antimetastatic agent.
Q-Index Code C1
Q-Index Status Provisional Code
Institutional Status UQ

Document type: Journal Article
Sub-type: Article (original research)
Collections: Official 2016 Collection
School of Chemistry and Molecular Biosciences
 
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