Lithium chloride antileukemic activity in acute promyelocytic leukemia is GSK-3 and MEK/ERK dependent

Zassadowski, Fabien; Pokorná, Kateřina; Ferre, N.; Guidez, Fabien; Llopis, Laura; Chourbagi, Oussama; Chopin, Martine; Poupon, Joël; Fenaux, Pierre; Padua, Rose Ann; Pla, Marika; Chomienne, Christine; Cassinat, Bruno

doi:10.1038/leu.2015.159

Cited by 21 publications

(16 citation statements)

References 45 publications

(58 reference statements)

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“…SOR applied to APL cells has been reported to reduce the number of cells [3,[16][17][18][19]. Consistent with our findings, lithium preventing carcinogenesis in APL cells and various cell lines has also been seen in current studies in the literature [20,21,15]. The effect of increasing apoptosis was stronger than the effect of decreasing total cell count.…”

Section: Discussionsupporting

confidence: 91%

The mechanism of apoptosis in human acute promyelocytic leukemia cells treated with sorafenib and lithium chloride

Ekinci¹

2019

Int J Med Biochem

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The mechanism of apoptosis in human acute promyelocytic leukemia cells treated with sorafenib and lithium chloride I n the last decade, considerable evidence has been presented that has helped to understand the molecular components that contribute to the pathogenesis of acute myeloblastic leukemia (AML) [1]. AML accounts for approximately 15% of childhood leukemia, which includes the acute promyelocytic leukemia (APL) subtype [2]. All-trans retinoic acid, anthracycline antibiotics, and arsenic trioxide (ATO) are effective agents used in the treatment of APL; however, other treatment options become important when drug resistance develops [3]. Apoptosis can be triggered by various signals that occur at the extracellular and cellular levels. Caspase-3 is a molecule involved in the death receptor-mediated apoptotic (extrinsic) pathway [4]. Although the pathways involved in the dif-Objectives: This study was an investigation of the mechanisms of sorafenib (SOR) and lithium chloride (LiCl), which cause apoptosis, in the acute promyelocytic leukemia (APL) HL-60 cell line. Methods: HL-60 cells were treated with 100 µM of SOR, LiCl, and a combination of the 2 drugs, and a control group was not treated. Cells were collected after a period of 24, 48, and 72 hours, and cell proliferation and the apoptotic index were assessed with a hemocytometer and flow cytometry analysis. The level of caspase-3, phospho-glycogen synthase kinase-3 beta (p-GSK-3β), phospho-protein kinase B (p-AKT), phospho-extracellular-signal-regulated kinase (p-ERK), p38, phospho-c-Jun (p-c-Jun), and phospho-inhibitor kappa B (p-IκBα) were analyzed using the enzyme-linked immunosorbent assay method. The effects of the drugs on cell ultrastructure were evaluated with a transmission electron microscope (TEM). Results: Single and combination drug administration decreased cell proliferation and increased the apoptosis rate (p<0.01 for both). The increase in apoptosis in the SOR+LiCl group was greater than that of the SOR group (p<0.01); however, there was no significant increase compared with the LiCl group. While both drugs increased the caspase-3 level (p<0.01 for both), LiCl increased caspase-3 activity more than SOR. Although p-GSK-3β levels decreased in the SOR group (p<0.01), levels increased in the LiCl group (p>0.05). Combined drug administration decreased the level of p-AKT and p38 (p<0.01 for both); however, it did not significantly affect the level of pERK , p-IκBα, or p-c-Jun (p>0.05). TEM examination revealed severe lytic cytoplasmic damage and apoptotic morphology, an indication of apoptosis. Conclusion: The results of this study demonstrated that in human APL cells treated with SOR and LiCl, increased apoptosis led to a decrease in tumor cells. This combination may become a preferred drug alternative for patients with APL and a mood disorder.

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Section: Discussionsupporting

confidence: 91%

The mechanism of apoptosis in human acute promyelocytic leukemia cells treated with sorafenib and lithium chloride

Ekinci¹

2019

Int J Med Biochem

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“…Even though the basis for the discrepancy with our results is unclear, accumulated research has shown that the outcome in cell proliferation can be cell type-, context- and stimulus-dependent. An anti-mitogenic action of lithium has been reported primarily in cancer cells from colon, neuroblastoma and leukemia [54–56]. In normal cells, on the contrary, both the action of lithium and that of GSK-3β inhibitors has been prevalently linked to an increase rather than a decrease in cell proliferation rates.…”

Section: Discussionmentioning

confidence: 99%

Lithium Reversibly Inhibits Schwann Cell Proliferation and Differentiation Without Inducing Myelin Loss

et al. 2016

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This study was undertaken to examine the bioactivity, specificity and reversibility of lithium’s action on the growth, survival, proliferation and differentiation of cultured Schwann cells (SCs). In isolated SCs, lithium promoted a state of cell cycle arrest that featured extensive cell enlargement and c-Jun downregulation in the absence of increased expression of myelin-associated markers. In addition, lithium effectively prevented mitogen-induced S-phase entry without impairing cell viability. When lithium was administered together with differentiating concentrations of cAMP analogs, a dramatic inhibition of the expression of the master regulator of myelination Krox-20 was observed. Likewise, lithium antagonized the cAMP-dependent expression of various myelin markers such as protein zero, periaxin and galactocerebroside and allowed SCs to maintain high levels of expression of immature SC markers even in the presence of high levels of cAMP and low levels of c-Jun. Most importantly, the inhibitory action of lithium on SC proliferation and differentiation was shown to be dose dependent, specific and reversible upon removal of lithium compounds. In SC-neuron cultures, lithium suppressed myelin sheath formation while preserving axonal integrity, SC-axon contact and basal lamina formation. Lithium was unique in its ability to prevent the onset of myelination without promoting myelin degradation or SC dedifferentiation. To conclude, our results underscored an unexpected antagonistic action of lithium on SC mitogenesis and myelin gene expression. We suggest that lithium represents an attractive pharmacological agent to safely and reversibly suppress the onset of SC proliferation, differentiation and myelination while maintaining the integrity of pre-existing myelinated fibers.

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“…Even though LiCl is widely used experimentally, the molecular mechanisms by which LiCl treatment regulates ERK phosphorylation have not yet been elucidated, various different responses having been obtained depending on the type of cell studied (Ref. 36).…”

Section: Discussionmentioning

confidence: 99%

FRZB and melusin, overexpressed in LGMD2A, regulate integrin β1D isoform replacement altering myoblast fusion and the integrin-signalling pathway

Jaka

Casas-Fraile

Azpitarte

et al. 2017

Expert Rev. Mol. Med.

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Limb-girdle muscular dystrophy type 2A (LGMD2A) is characterised by muscle wasting and progressive degeneration of proximal muscles because of mutations in the CAPN3 gene. However, the underlying pathophysiological mechanisms of muscle degeneration are still not well understood. The objective of this study was to assess the relevance of genes with differential expression in the muscle of LGMD2A patients. For this purpose, we analysed their in vitro expression in primary cultures of human myoblasts and myotubes. Abnormal fusion was observed in the myotubes of these patients, which may be explained by the lack of physiological replacement of integrin β1D. Owing to this observation, we focused on deregulated genes coding proteins that directly interact with integrin, ITGB1BP2 and CD9, as well as FRZB gene, because of its in vitro upregulation in myotubes. Silencing studies established that these genes are closely regulated, CD9 and FRZB being positive regulators of the expression of ITGB1BP2, and in turn, this gene being a negative regulator of the expression of FRZB. Interestingly, we observed that FRZB regulates integrin β1D expression, its silencing increasing integrin β1D expression to levels similar to those in controls. Finally, the administration of LiCl, an enhancer of the Wnt-signalling pathway showed similar experimentally beneficial effects, suggesting FRZB silencing or LiCl administration as potential therapeutic targets, though further studies are required.

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Lithium chloride antileukemic activity in acute promyelocytic leukemia is GSK-3 and MEK/ERK dependent

Cited by 21 publications

References 45 publications

The mechanism of apoptosis in human acute promyelocytic leukemia cells treated with sorafenib and lithium chloride

The mechanism of apoptosis in human acute promyelocytic leukemia cells treated with sorafenib and lithium chloride

Lithium Reversibly Inhibits Schwann Cell Proliferation and Differentiation Without Inducing Myelin Loss

FRZB and melusin, overexpressed in LGMD2A, regulate integrin β1D isoform replacement altering myoblast fusion and the integrin-signalling pathway

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