Arsenic trioxide synergistically potentiates the cytotoxic effect of fludarabine in chronic lymphocytic leukemia cells by further inactivating the Akt and ERK signaling pathways

Lozano-Santos, Carol; Amigo-Jiménez, Irene; Nova-Gurumeta, Sara; Pérez-Sanz, Nuria; García-Pardo, Ángeles; García-Marco, José A.

doi:10.1016/j.bbrc.2015.04.007

Cited by 6 publications

(5 citation statements)

References 28 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In vitro results are promising, but clinical success has been limited by the higher doses of As 2 O 3 required for induction of non-acute promyelocytic leukemia tumor cell death (Platanias, 2009). Considerable effort has been made to target kinase pathways that are activated by As 2 O 3 to increase the efficacy of this agent (Verma et al, 2002;Giafis et al, 2006;Dolniak et al, 2008;McNeer et al, 2010;Galvin et al, 2013;Beauchamp et al, 2015;Lozano-Santos et al, 2015). It may be that the kinase pathways responsible for phosphorylation of Tyr920 and Ser921 of MRP1 overlap with the kinase pathways activated by As 2 O 3 .…”

Section: Discussionmentioning

confidence: 99%

Arsenic Triglutathione [As(GS)₃] Transport by Multidrug Resistance Protein 1 (MRP1/ABCC1) Is Selectively Modified by Phosphorylation of Tyr920/Ser921 and Glycosylation of Asn19/Asn23

et al. 2016

View full text Add to dashboard Cite

The ATP-binding cassette (ABC) transporter multidrug resistance protein 1 (MRP1/ABCC1) is responsible for the cellular export of a chemically diverse array of xenobiotics and endogenous compounds. Arsenic, a human carcinogen, is a high-affinity MRP1 substrate as arsenic triglutathione [As(GS) 3 ]. In this study, marked differences in As(GS) 3 transport kinetics were observed between MRP1-enriched membrane vesicles prepared from human embryonic kidney 293 (HEK) (K m 3.8 mM and V max 307 pmol/mg per minute) and HeLa (K m 0.32 mM and V max 42 pmol/mg per minute) cells. Mutant MRP1 lacking N-linked glycosylation [Asn19/23/1006Gln; sugar-free (SF)-MRP1] expressed in either HEK293 or HeLa cells had low K m and V max values for As(GS) 3 , similar to HeLa wild-type (WT) MRP1. When prepared in the presence of phosphatase inhibitors, both WT-and SF-MRP1-enriched membrane vesicles had a high K m value for As(GS) 3 (3-6 mM), regardless of the cell line. Kinetic parameters of As(GS) 3 for HEKAsn19/23Gln-MRP1 were similar to those of HeLa/HEK-SF-MRP1and HeLa-WT-MRP1, whereas those of single glycosylation mutants were like those of HEK-WT-MRP1. Mutation of 19 potential MRP1 phosphorylation sites revealed that HEK-Tyr920Phe/ Ser921Ala-MRP1 transported As(GS) 3 like HeLa-WT-MRP1, whereas individual HEK-Tyr920Phe-and -Ser921Ala-MRP1 mutants were similar to HEK-WT-MRP1. Together, these results suggest that Asn19/Asn23 glycosylation and Tyr920/Ser921 phosphorylation are responsible for altering the kinetics of MRP1-mediated As(GS) 3 transport. The kinetics of As(GS) 3 transport by HEK-Asn19/23Gln/Tyr920Glu/Ser921Glu were similar to HEK-WT-MRP1, indicating that the phosphorylation-mimicking substitutions abrogated the influence of Asn19/23Gln glycosylation. Overall, these data suggest that cross-talk between MRP1 glycosylation and phosphorylation occurs and that phosphorylation of Tyr920 and Ser921 can switch MRP1 to a lower-affinity, higher-capacity As(GS) 3 transporter, allowing arsenic detoxification over a broad concentration range.

show abstract

Section: Discussionmentioning

confidence: 99%

Arsenic Triglutathione [As(GS)₃] Transport by Multidrug Resistance Protein 1 (MRP1/ABCC1) Is Selectively Modified by Phosphorylation of Tyr920/Ser921 and Glycosylation of Asn19/Asn23

et al. 2016

View full text Add to dashboard Cite

show abstract

“…We previously showed that ATO could constitute an efficient treatment in CLL, particularly in combined therapies [ 10 , 16 , 28 ]. To further explore the potential clinical use of this agent, we have now studied the influence of bone marrow stromal cells on the response of CLL cells to ATO.…”

Section: Discussionmentioning

confidence: 99%

Bone marrow stroma-induced resistance of chronic lymphocytic leukemia cells to arsenic trioxide involves Mcl-1 upregulation and is overcome by inhibiting the PI3Kδ or PKCβ signaling pathways

et al. 2015

Self Cite

View full text Add to dashboard Cite

CLL remains an incurable disease in spite of the many new compounds being studied. Arsenic trioxide (ATO) induces apoptosis in all CLL cell types and could constitute an efficient therapy. To further explore this, we have studied the influence of stromal cells, key components of the CLL microenvironment, on the response of CLL cells to ATO. Bone marrow stromal cells induced CLL cell resistance to 2 μM ATO and led to activation of Lyn, ERK, PI3K and PKC, as well as NF-κB and STAT3. Mcl-1, Bcl-xL, and Bfl-1 were also upregulated after the co-culture. Inhibition experiments indicated that PI3K and PKC were involved in the resistance to ATO induced by stroma. Moreover, idelalisib and sotrastaurin, specific inhibitors for PI3Kδ and PKCβ, respectively, inhibited Akt phosphorylation, NF-κB/STAT3 activation and Mcl-1 upregulation, and rendered cells sensitive to ATO. Mcl-1 was central to the mechanism of resistance to ATO, since: 1) Mcl-1 levels correlated with the CLL cell response to ATO, and 2) blocking Mcl-1 expression or function with specific siRNAs or inhibitors overcame the protecting effect of stroma. We have therefore identified the mechanism involved in the CLL cell resistance to ATO induced by bone marrow stroma and show that idelalisib or sotrastaurin block this mechanism and restore sensibility to ATO. Combination of ATO with these inhibitors may thus constitute an efficient treatment for CLL.

show abstract

“…It had been reported that arsenic-induced apoptosis of cancer cells was correlated with inhibition of ERK ( 29 – 32 ). Furthermore, arsenic inhibition of ERK signaling pathway in human leukemia cells was also verified as a fact ( 7 , 10 , 24 , 33 ). Likewise, decreased levels of both Ras and p-ERK were shown in cancer cells ( Fig.…”

Section: Discussionmentioning

confidence: 76%

“…It had been postulated that ERK was consequently a participant in arsenic-induced apoptosis ( 7 , 8 ). In all these studies, however, not all scholars were in agreement on the issue of arsenic mediating ERK signaling.…”

Section: Introductionmentioning

confidence: 99%

A systematic review and meta-analysis of bidirectional effect of arsenic on ERK signaling pathway

Wei

et al. 2018

Mol Med Report

View full text Add to dashboard Cite

Arsenic is a toxic metal, which ultimately leads to cell apoptosis. ERK is considered a key transcriptional regulator of arsenic-induced apoptosis. Due to a few controversial issues about arsenic-mediated extracellular signal-regulated MAP kinases (ERK) signaling, a meta-analysis was performed. Subgroup analyses demonstrated that high doses (≥2 µmol/l) of arsenic increased the expression of Ras, ERK, ERK1, ERK2, phosphorylated (p)-ERK, p-ERK1, and p-ERK2, while low doses (<2 µmol/l) decreased the expression of Ras, ERK1, p-ERK, and p-ERK2 when compared to control groups. Long term exposure (>24 h) to arsenic led to inhibition of expression of ERK1, p-ERK1, and p-ERK2, whereas short-term exposure (≤24 h) triggered the expression of ERK1, ERK2, p-ERK, p-ERK1, and p-ERK2. Furthermore, normal cells exposed to arsenic exhibited higher production levels of Ras and p-ERK. Conversely, exposure of cancer cells to arsenic showed a lower level of production of Ras and p-ERK as well as higher level of p-ERK1 and p-ERK2 as compared to control group. Short-term exposure of normal cells to high doses of arsenic may promote ERK signaling pathway. In contrast, long-term exposure of cancer cells to low doses of arsenic may inhibit ERK signaling pathway. This study may be helpful in providing a theoretical basis for the diverging result of arsenic adverse effects on one hand and therapeutic mechanisms on the other concerning arsenic-induced apoptosis.

show abstract

Arsenic trioxide synergistically potentiates the cytotoxic effect of fludarabine in chronic lymphocytic leukemia cells by further inactivating the Akt and ERK signaling pathways

Cited by 6 publications

References 28 publications

Arsenic Triglutathione [As(GS)₃] Transport by Multidrug Resistance Protein 1 (MRP1/ABCC1) Is Selectively Modified by Phosphorylation of Tyr920/Ser921 and Glycosylation of Asn19/Asn23

Arsenic Triglutathione [As(GS)₃] Transport by Multidrug Resistance Protein 1 (MRP1/ABCC1) Is Selectively Modified by Phosphorylation of Tyr920/Ser921 and Glycosylation of Asn19/Asn23

Bone marrow stroma-induced resistance of chronic lymphocytic leukemia cells to arsenic trioxide involves Mcl-1 upregulation and is overcome by inhibiting the PI3Kδ or PKCβ signaling pathways

A systematic review and meta-analysis of bidirectional effect of arsenic on ERK signaling pathway

Contact Info

Product

Resources

About

Arsenic trioxide synergistically potentiates the cytotoxic effect of fludarabine in chronic lymphocytic leukemia cells by further inactivating the Akt and ERK signaling pathways

Cited by 6 publications

References 28 publications

Arsenic Triglutathione [As(GS)3] Transport by Multidrug Resistance Protein 1 (MRP1/ABCC1) Is Selectively Modified by Phosphorylation of Tyr920/Ser921 and Glycosylation of Asn19/Asn23

Arsenic Triglutathione [As(GS)3] Transport by Multidrug Resistance Protein 1 (MRP1/ABCC1) Is Selectively Modified by Phosphorylation of Tyr920/Ser921 and Glycosylation of Asn19/Asn23

Bone marrow stroma-induced resistance of chronic lymphocytic leukemia cells to arsenic trioxide involves Mcl-1 upregulation and is overcome by inhibiting the PI3Kδ or PKCβ signaling pathways

A systematic review and meta-analysis of bidirectional effect of arsenic on ERK signaling pathway

Contact Info

Product

Resources

About

Arsenic Triglutathione [As(GS)₃] Transport by Multidrug Resistance Protein 1 (MRP1/ABCC1) Is Selectively Modified by Phosphorylation of Tyr920/Ser921 and Glycosylation of Asn19/Asn23

Arsenic Triglutathione [As(GS)₃] Transport by Multidrug Resistance Protein 1 (MRP1/ABCC1) Is Selectively Modified by Phosphorylation of Tyr920/Ser921 and Glycosylation of Asn19/Asn23