Raf/MEK/ERK signaling inhibition enhances the ability of dequalinium to induce apoptosis in the human leukemic cell line K562

Abstract

Delocalized lipophilic cations, such as dequalinium (DQA), selectively accumulate in mitochondria and display anticancer activity in cells from different malignancies. Previous studies in K562 human leukemic cells indicate that DQA causes cell damage as a consequence of an early disturbance in the mitochondrial function, inducing oxidative stress. These cells turned out to be resistant to apoptosis and died by necrosis when treated with high DQA concentrations (20 μmol/L) for long time periods (48 h). Resistance of K562 cells to DQA-induced apoptosis could be eliminated by inhibition of the kinase activity of the Bcr-Abl protein with imatinib. In this paper, we have studied the effect of DQA on the Raf/MEK/ERK1/2 and PI3K/Akt signal transduction pathways in K562 cells. Our data suggest a DQA downregulatory activity on both ERK1/2 and PI3K protein kinase activity supporting an interaction between both proteins. Moreover, inhibition of ERK1/2 with U0126 enhanced the ability of DQA to potentiate imatinib-induced apoptosis, suggesting a role of the Raf/MEK/ERK pathway and the Bcr-Abl tyrosine kinase in the K562 cell survival. This study contributes to a better understanding of the action mechanism of DQA on K562 cells and encourages the study of DQA in combination with other agents for improving the efficacy of targeted therapies and overcoming resistance to chemotherapeutic agents.

MAPK signaling pathways regulate mitochondrial-mediated apoptosis induced by isoorientin in human hepatoblastoma cancer cells

“…5). These results suggest that the MAPK signaling pathway is the initiating signal of the mitochondrial-mediated apoptosis induced by in HepG2 cells which is consistent with previous studies, such as the inhibition of ERK1/2 signaling enhances the ability of dequalinium to induce apoptosis in the human leukemic cell line K562 (Sancho et al, 2012), butyrate induces cell apoptosis through activation of JNK kinase pathway in human colon cancer RKO cells , p38 and JNK modulate the expression and translocation of Bcl-2 and Bax, cytochrome c release and caspase-3 activation in apoptotic cells Xie et al, 2010;Laethem et al, 2004;Putcha et al, 2003). That is mainly attributed to the effects of JNK and p38 kinase.…”

“…MAPK has been implicated in a wide array of physiological processes including cell growth, differentiation and apoptosis. Numerous investigations have demonstrated that ERK1/2 is required for survival signaling, and inhibition of ERK1/2 plays a crucial role in apoptosis induced by various stimuli, such as dequalinium (Sancho et al, 2012), paclitaxel (Xu et al, 2009), sorafenib (Liu et al, 2006), lovastatin (Wu et al, 2004), and taxol (Seidman et al, 2001). In contrast to ERK1/2, activation of JNK and p38 have been implicated in apoptosis induced by various stimuli or anticancer drug, such as xanthohumol (Festa et al, 2011), glutamate (Zhang et al, 2011a), thymoquinone (El-Najjar et al, 2010), anandamide (Michela et al, 2006), resveratrol (Su et al, 2005;She et al, 2001), and nitric oxide (Kim et al, 2002).…”

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

“…Moreover, these inhibitors potentiate both the inhibitory effect on Raf/MEK/ERK1/2 and PI3K/Akt pathways and the pro-apoptotic effect of DQA mainly at a high 20 M concentration. These results are similar to those previously obtained in K562 cells [20]. These results also agree with that obtained in cotreatments with ATO plus a PI3K inhibitor or siRNA knock-down of Akt which potentiated apoptosis in NB4 and other leukemia cell lines such as CEM, Jurkat, MOLT-4 and HL-60 cells [34][35][36][37].…”

“…Antileukemic properties of DQA against the human leukemia cell lines, NB4 derived from acute promyelocytic leukemia, and K562, derived from chronic myeloid leukemia, are being studied in our group. We have reported the ability of DQA as a selective and potential antileukemic agent by interfering mitochondrial function, decreasing ATP and inducing oxidative stress which results in apoptosis by the intrinsic mitochondrial pathway [17][18][19][20]. Our previous results also support a cytotoxic effect of DQA on peripheral blood mononuclear cells from B-CLL patients that was higher than those from healthy donors [16].…”

Neferine in the Lotus Plumule Potentiates the Antitumor Effect of Imatinib in Primary Chronic Myeloid Leukemia Cells In Vitro

“…Activated Erk can phosphorylate various substrates, including nuclear transcription factors and protein kinases in the nucleus to regulate gene transcription, thereby promoting cell proliferation, differentiation and survival (Huang, Xiao, & Huang, ; Maemura et al., ; Xiao et al., ). In CML cell line K562, inhibiting Erk can induce apoptosis (Sancho et al., ). In this study, phosphorylation of Erk1/2 was suppressed by neferine alone or treatment of neferine combined with imatinib, suggesting that neferine is a potential Erk1/2 inhibitor in CML treatment.…”