Dequalinium induces cytotoxicity in human leukemia NB4 cells by downregulation of Raf/MEK/ERK and PI3K/Akt signaling pathways and potentiation of specific inhibitors of these pathways

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• 作者：Ana I. Garcí ; a-Pé ; rez^a ; ^{ana.garcia@uah.es" class="auth_mail} ; Eva Galeano^b ; Elena Nieto^a ; M. Cristina Estañ ; ^c ; Pilar Sancho^a
• 关键词：APL ; acute promyelocytic leukemia ; ATO ; arsenic trioxide ; ATRA ; all-trans retinoic acid ; DQA ; dequalinium ; GSH ; glutathione ; NB4 ; human acute promyelocytic leukemia derived cell line ; PML ; promyelocytic leukemia ; ROS ; reactive oxygen species
• 刊名：Leukemia Research
• 出版年：July 2014
• 年：2014
• 卷：38
• 期：7
• 页码：795-803
• 全文大小：1931 K

文摘

Delocalized lipophilic cation dequalinium (DQA) selectively accumulates in mitochondria and displays anticancer activity in different malignancies. Our previous studies indicate a DQA-induced cytotoxicity in human acute promyelocytic leukemia NB4 cells by early disturbance in mitochondrial function and oxidative stress. This study shows the ability of DQA to downregulate Raf/MEK/ERK1/2 and PI3K/Akt signaling pathways in NB4 cells which leads to cell death by apoptosis and/or necrosis. Moreover, DQA potentiates the action of specific inhibitors of these pathways. These DQA effects could be mediated by redox regulation of Akt. Our results contribute to a better understanding of the cytotoxic DQA mechanism on leukemia cells and encourage the performance of further studies in combination with other agents such as kinase inhibitors for improving the efficacy of therapies against acute promyelocytic leukemia.