Novel mechanism of Cytotoxicity for the selective Selenosemicarbazone, 2-Acetylpyridine 4,4-Dimethyl-3- selenosemicarbazone (Ap44mSe): Lysosomal Membrane Permeabilization

Zaynab Al-Eisawi, Christian Stefani, Patric J Jansson, Akanksha Arvind, Philip C Sharpe, Maram T Bashaa, George Mina Iskander, Naresh Kumar, Zaklina Kovacevic, Darius J R Lane, Sumit Sahni, Paul V Bernhardt, Des R. Richardson, Danuta S. Kalinowski

Research output: Contribution to journalArticlepeer-review

39 Citations (Scopus)

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.
Original languageEnglish
Pages (from-to)294-312
Number of pages19
JournalJournal of Medicinal Chemistry
Volume59
Issue number1
Early online dateDec 2015
DOIs
Publication statusPublished - 2016

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