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

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.