著者

袁 博 高木 教夫 岡崎 真理 平野 俊彦

雑誌

日本薬学会第141年会(広島)

巻号頁・発行日

2021-02-01

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Arsenic and its compounds are widely distributed in the environment and exist in organic and inorganic forms. Although as a well-known poison, arsenic has been used medicinally for over 2,000 years. Notably, administration of trivalent arsenic derivatives (arsenite, AsIII) such as arsenic trioxide (ATO) has demonstrated a remarkable efficacy in the treatment of acute promyelocytic leukemia (APL), the vast majority of which is characterized by the promyelocytic leukemia (PML)-retinoic acid receptors (RARα) fusion caused by the t(15;17) translocation. Differentiation associated with the degradation of fusion protein PML-RARα, apoptosis induction, cell cycle arrest as well as autophagy induction have been shown to be linked to the therapeutic effects of ATO against APL. Several research groups including us have conducted detailed pharmacokinetic studies of ATO in APL by using biological samples such as peripheral blood, cerebrospinal fluid, bone marrow from patients. Aquaporin 9 and multidrug resistance-associated proteins (MRP1/MRP2/MRP4) have been reported to play pivotal roles in the uptake/efflux of arsenic, respectively. Here, we are going to introduce the mechanisms underlying the antitumor activity of AsIII and provide new insights into its potential novel application in terms of combinational treatment. Despite organic arsenicals mainly contained in seafood are known to be harmless, a novel organic arsenical, S-dimethylarsino-glutathione (darinaparsin, Dar), synthesized by conjugating dimethylarsenic to glutathione, has shown promising anticancer activity and is currently in use in human clinical trials in cancer patients. It has been demonstrated that Dar has overlapping, but distinct, signaling mechanisms of cell death induced by AsIII. We also provide some recent evidence of the cytocidal effect of Dar on several leukemia cell lines for understanding the arsenic compound in comparison to AsIII.