2-Aminophenoxazine-3-one and 2-amino-4,4α-dihydro-4α,7-dimethyl-3H-phenoxazine-3-one cause cellular apoptosis by reducing higher intracellular pH in cancer cells

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概要

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• We examined intracellular pH (pHi) of ten cancer cell lines derived from different organs and two normal cell lines including human embryonic lung fibroblast cells (HEL) and human umbilical vein endothelial cells (HUVEC) in vitro, and found that pHi of most of these cancer cells was evidently higher (pH 7.5 to 7.7) than that of normal cells (7.32 and 7.44 for HEL and HUVEC, respectively) and that of primary leukemic cells and erythrocytes hitherto reported (≤7.2). Higher pHi in these cancer cells could be related to the Warburg effect in cancer cells with enhanced glycolytic metabolism. Since reversal of the Warburg effect may perturb intracellular homeostasis in cancer cells, we looked for compounds that cause extensive reduction of pHi, a major regulator of the glycolytic pathway and its associated metabolic pathway. We found that phenoxazine compounds, 2-aminophenoxazine-3-one (Phx-3) and 2-amino-4,4α-dihydro-4α,7-dimethyl-3H-phenoxazine-3-one (Phx-1) caused a rapid and drastic dose-dependent decrease of pHi in ten different cancer cells within 30 min, though the extent of the decrease of pHi was significantly larger for Phx-3 (ΔpHi = 0.6 pH units or more for 100 µM Phx-3) than for Phx-1 (ΔpHi = 0.1 pH units or more for 100 µM Phx-1). This rapid and drastic decrease of pHi in a variety of cancer cells caused by Phx-3 and Phx-1 possibly perturbed their intracellular homeostasis, and extensively affected the subsequent cell death, because these phenoxazines exerted dose-dependent proapoptotic and cytotoxic effects on these cells during 72 h incubation, confirming a causal relationship between ΔpHi and cytotoxic effects due to Phx-3 and Phx-1. Phx-3 and Phx-1 also reduced pHi of normal cells including HEL and HUVEC, although they exerted less proapoptotic and cytotoxic effects on these cells than on cancer cells. Drugs such as Phx-3 and Phx-1 that reduce pHi and thereby induce cellular apoptosis might serve as benevolent anticancer drugs.(Edited by Takao SEKIYA, M.J.A.)

• 日本学士院の論文

著者

• Tomoda Akio

  Department of Biochemistry and Intractable Immune System Disease Research Center, Tokyo Medical Univ

• Akiyama Shin-ichi

  東京医科大学 内科学第3

• Akiyama Shin-ichi

  Department Of Cancer Chemotherapy Institute For Cancer Research

• CHE Xiao-Fang

  Department of Cancer Chemotherapy, Institute for Cancer Research Kagoshima University

• Che Xiao

  Graduate School Of Medical And Dental Sciences Kagoshima University

• Che Xiao-fang

  Department Of Cancer Chemotherapy Institute For Cancer Research Kagoshima University

• Tomoda Akio

  Department Of Biochemistry And Intractable Immune System Disease Research Center Tokyo Medical Unive

• Akiyama Shinichi

  Graduate School Of Medical And Dental Sciences Kagoshima University

• ZHENG Chun-Lei

  Department of Medical Oncology, Cancer Hospital, Fudan University

• Che Xiao-fang

  Department Of Biochemistry Tokyo Medical University

• Che Xiao-Fang

  Department of Biochemistry, Tokyo Medical University

• TOMODA Akio

  Department of Biochemistry, Tokyo Medical University

• AKIYAMA Shin-Ichi

  Department of Medical Oncology, Institute of Health Biosciences, The University of Tokushima, Graduate School

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