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

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.

A novel class of thiosemicarbazones show multi-functional activity for the treatment of Alzheimer's disease

“…Although the Cu complex of Dp44mT showed similar antiproliferative activity to its free ligand, Donepezil in the presence of Cu demonstrated increased antiproliferative activity relative to Donepezil alone ( Table 1). As shown previously [62], the Fe complexes of DFO and Dp44mT showed significantly (p < 0.001) decreased anti-proliferative activity compared to their respective ligands ( Table 1). The anti-proliferative efficacy of Donepezil in the presence of iron was similar to that observed for Donepezil alone (>100 µM; Table 1).…”

“…The anti-proliferative activity of the copper and iron complexes of the controls, DFO, Dp44mT and Donepezil, were also assessed. The Cu complex of DFO showed a significant (p < 0.001) increase in anti-proliferative activity relative to the free ligand, as observed previously [62]. Although the Cu complex of Dp44mT showed similar antiproliferative activity to its free ligand, Donepezil in the presence of Cu demonstrated increased antiproliferative activity relative to Donepezil alone ( Table 1).…”

BODIPY-Decorated Nanoscale Covalent Organic Frameworks for Photodynamic Therapy

“…As shown in Figures 8C and 8D, a significant intracellular red dot fluorescence was observed due to the formation of protonated AO in the intact lysosomes (pH 4–5), implying that 3 and 5 did not damage the lysosomes in dark. However, the intracellular red fluorescence was weakened or even disappeared under light irradiation, which demonstrated that AO was released from the lysosome into the cytoplasm (pH ∼7.2), and moreover, deprotonated in the weak alkaline environment to emit diffuse green fluorescence (Al-Eisawi et al., 2016, Boya and Kroemer, 2008). This observation suggested that 3- and 5 -triggered 1 O 2 can induce LMP, and effectively promoted cell death via lysosome-associated pathway.…”

Revisiting the thiosemicarbazonecopper(II) reaction with glutathione. Activity against colorectal carcinoma cell lines

“…The anticancer and antioxidant activities of thiosemicarbazones are clearly affected by their structural formulae and interaction with metals [130,131,132]. The antiproliferative activity of the ligands HPTSC and HPTSC* and their Cu II complexes has been evaluated after 24 h of drug treatment, using MTT assay and the results are summarized in Table 3 cellular line, where the compound 1 showed higher value of cytotoxicity than compound 2 [37].…”