TY - JOUR
T1 - Novel mechanism of Cytotoxicity for the selective Selenosemicarbazone, 2-Acetylpyridine 4,4-Dimethyl-3- selenosemicarbazone (Ap44mSe)
T2 - Lysosomal Membrane Permeabilization
AU - Al-Eisawi, Zaynab
AU - Stefani, Christian
AU - Jansson, Patric J
AU - Arvind, Akanksha
AU - Sharpe, Philip C
AU - Bashaa, Maram T
AU - Iskander, George Mina
AU - Kumar, Naresh
AU - Kovacevic, Zaklina
AU - Lane, Darius J R
AU - Sahni, Sumit
AU - Bernhardt, Paul V
AU - Richardson, Des R.
AU - Kalinowski, Danuta S.
N1 - Includes bibliographical references.
PY - 2016
Y1 - 2016
N2 - 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.
AB - 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.
KW - Pyridoxal isonicotinoyl hydrazone
KW - Ribonucleotide reductase inhibitor
U2 - 10.1021/acs.jmedchem.5b01399
DO - 10.1021/acs.jmedchem.5b01399
M3 - Article
C2 - 26645570
SN - 0022-2623
VL - 59
SP - 294
EP - 312
JO - Journal of Medicinal Chemistry
JF - Journal of Medicinal Chemistry
IS - 1
ER -