The Calcium‐Chelating Capability of Tetrahydrofuranic Moieties Modulates the Cytotoxicity of Annonaceous Acetogenins

Abstract

Forced entry: NMR spectroscopy and isothermal titration calorimetry show that calcium ions are chelated by the hydroxylated THF ring of acetogenins, which results in formation of complexes that aid the Ca2+ cations in penetrating cell membranes and in elevating the intracellular calcium level (see picture). This disruption of intracellular calcium homeostasis induces mitochondrial depolarization and mediates cell toxicity.

Mechanistic Study of Tetrahydrofuran- acetogenins In Triggering Endoplasmic Reticulum Stress Response-apotoposis in Human Nasopharyngeal Carcinoma

“…Microarray analysis data of squamostatin A-treated NPC-TW01 cells suggested that THF-ACG may augment the activation of ESR and was later confirmed by real-time PCR, Western blot analysis and siRNA knockdown experiments. Contrast to a previous report18, our study showed that the ERS response induced by THF-ACG was independent of extracellular Ca 2+ , although the presence of extracellular Ca 2+ enhanced the antiproliferative effect of ACGs. In vivo experiments showed that squamostatin A has a good pharmacokinetic profile and anticancer properties against NPC growth in the s.c. xenograft murine experiments.…”

“…suggested that ACG treatment induces a dramatic increase in cytosolic Ca 2+ , resulting in tumor cell death18. Our results also showed that cytosolic Ca 2+ levels were elevated by 50~120% after treatment with all three THF-ACGs.…”

“…hypothesized that ACGs could chelate and transport Ca 2+ from the extracellular culture medium across the cell membrane, leading to increased cytosolic Ca 2+ levels and ultimately resulting in cell death18. To investigate the importance of extracellular Ca 2+ , NPC-TW01 cells were cultured in Ca 2+ -free medium for 24 hours, then treated with squamostatin A, and the change in the IC 50 values for squamostatin A against NPC-TW01 cell growth, cytosolic Ca 2+ concentrations, the expression of ESR-related genes and caspase-12 activity were measured.…”

“…However, after more than three decades of intensive research, with over 400 natural and synthetic ACGs tested12, the mechanism of action remains largely elusive. Several molecular pathways have been proposed, such as disruption of mitochondrial complex I13, the generation of superoxide anion and hydrogen peroxide14, decreases in both cAMP and cGMP levels15, the induction of cell-cycle arrest1617 or apoptotic cell death induced by elevated cytosolic Ca 2+  18. However, none of these mechanisms are able to fully explain the anti-tumor properties observed of ACGs19.…”

ZnII Complexes for Bioimaging and Correlated Applications

“…Generally,l anthanide ions such as Eu III and Tb III , [5][6][7] group VIII element ions includingI r III , Ru II and Pt II ,a nd other transition metal ions with d 0 ,d 5 and d 10 electronic configurations were usually involved in bio-labels to elicit metal-organic coordination with strong one-and twophoton fluorescence capabilities. [8][9][10] However,m ost of these elements exhibit high toxicity,w hich resultsi nu nforeseen reactions as well as large invasive effects in biological applications. [11,12] Several reviewsh ave excellently summarized the chemicald esign of transition metals and their luminescence cellular and biomolecular imaging applications.…”