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

  • J Med Chem. 2016 Jan 14;59(1):294-312. doi: 10.1021/acs.jmedchem.5b01399.
Zaynab Al-Eisawi  1 ,  Christian Stefani  1 ,  Patric J Jansson  1 ,  Akanksha Arvind  1 ,  Philip C Sharpe  2 ,  Maram T Basha  2 ,  George M Iskander  3 ,  Naresh Kumar  3 ,  Zaklina Kovacevic  1 ,  Darius J R Lane  1 ,  Sumit Sahni  1 ,  Paul V Bernhardt  2 ,  Des R Richardson  1 ,  Danuta S Kalinowski  1
Affiliations
  • 1. Molecular Pharmacology and Pathology Program, Department of Pathology and Bosch Institute, The University of Sydney , Sydney, Level 5, Blackburn Building (D06)New South Wales 2006, Australia.
  • 2. School of Chemistry and Molecular Biosciences, University of Queensland , Brisbane, Queensland 4072, Australia.
  • 3. School of Chemistry, University of New South Wales , Sydney, New South Wales 2052, Australia.
PMID: 26645570 DOI: 10.1021/acs.jmedchem.5b01399
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.

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