2023-09-14 アリゾナ大学
◆がん細胞は鉄に依存し、急速な増殖に必要なため、通常の細胞よりも鉄を多く必要とします。研究者は、鉄を悪性細胞内で捉えるための化合物を設計し、細胞内でのみ活性化されるようにしました。この新戦略は、鉄の利用可能性を減少させ、がんの成長を停止する方法として期待されています。
<関連情報>
- https://news.arizona.edu/story/uarizona-cancer-center-researchers-discover-iron-targeting-approaches-halt-proliferation
- https://pubs.acs.org/doi/10.1021/jacs.3c02033?ref=pdf
哺乳類細胞における抗増殖性ホルマザンキレーター放出のためのテトラゾリウムカチオンの設計 Design of Tetrazolium Cations for the Release of Antiproliferative Formazan Chelators in Mammalian Cells
Zoufeng Xu, Yu-Shien Sung, and Elisa Tomat
Journal of the American Chemical Society Published:July 6, 2023
DOI:https://doi.org/10.1021/jacs.3c02033
Abstract
Cancer cells generally present a higher demand for iron, which plays crucial roles in tumor progression and metastasis. This iron addiction provides opportunities to develop broad spectrum anticancer drugs that target iron metabolism. In this context, prochelation approaches are investigated to release metal-binding compounds under specific conditions, thereby limiting off-target toxicity. Here, we demonstrate a prochelation strategy inspired by the bioreduction of tetrazolium cations widely employed to assess the viability of mammalian cells. We designed a series of tetrazolium-based compounds for the intracellular release of metal-binding formazan ligands. The combination of reduction potentials appropriate for intracellular reduction and an N-pyridyl donor on the formazan scaffold led to two effective prochelators. The reduced formazans bind as tridentate ligands and stabilize low-spin Fe(II) centers in complexes of 2:1 ligand-to-metal stoichiometry. The tetrazolium salts are stable in blood serum for over 24 h, and antiproliferative activities at micromolar levels were recorded in a panel of cancer cell lines. Additional assays confirmed the intracellular activation of the prochelators and their ability to affect cell cycle progression, induce apoptotic death, and interfere with iron availability. Demonstrating the role of iron in their intracellular effects, the prochelators impacted the expression levels of key iron regulators (i.e., transferrin receptor 1 and ferritin), and iron supplementation mitigated their cytotoxicity. Overall, this work introduces the tetrazolium core as a platform to build prochelators that can be tuned for activation in the reducing environment of cancer cells and produce antiproliferative formazan chelators that interfere with cellular iron homeostasis.
