The multikinase inhibitor Sorafenib displays significant antiproliferative effects and induces apoptosis via caspase 3, 7 and PARP in B- and T-lymphoblastic cells

Schult, Catrin; Dahlhaus, Meike; Ruck, Sabine; Sawitzky, Mandy; Amoroso, Francesca; Lange, Sandra; Etro, Daniela; Glass, Äenne; Fuellen, Georg; Boldt, Sonja; Wolkenhauer, Olaf; Neri, Luca M.; Freund, Mathias; Junghanß, Christian

doi:10.1186/1471-2407-10-560

Cited by 46 publications

(43 citation statements)

References 45 publications

(54 reference statements)

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“…In a study published by Ki et al [27], it was confirmed that apoptosis occurred via the caspase-linked pathway and that drug-induced apoptosis was reduced when a caspase-3 inhibitor was added to HL-60 cells. Our study with leukemic cell lines treated with SOR revealed increased caspase-3 activation, which was consistent with previous results [3,17,19]. LiCl applied to leukemic cell lines has also been demonstrated to prompt an apoptotic response through increased caspase-3 activation [21].…”

Section: Discussionsupporting

confidence: 93%

“…We found a time-dependent decrease in tumor cell proliferation with the administration of the drugs, and binary drug therapy caused the greatest reduction. 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].…”

Section: Discussionsupporting

confidence: 92%

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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: 93%

Section: Discussionsupporting

confidence: 92%

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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“…Both activated caspase-8 and caspase-9 activate common downstream caspases, mainly caspase-3 and caspase-7, and then apoptosis takes place [31]. PARP is reported to be one of the main cleavage targets of caspase-3 in vivo [32]. It was also shown that caspase 7, which shares the same substrate preference as caspase 3, can cleave PARP more efficiently [33].…”

Section: Discussionmentioning

confidence: 92%

The Novel H7N9 Influenza A Virus NS1 Induces p53-Mediated Apoptosis of A549 Cells

Yan

Wang

et al. 2016

Cell Physiol Biochem

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Background: H7N9, emerged as an avian influenza virus outbreak in Eastern China in early 2013, and represented another major threat to global health. Roles of its NS1 protein, an essential viral factor, in regulating apoptosis remain unknown. Methods: Apoptotic effect and features of H7N9/NS1 in the human A549 alveolar basal epithelial cell line were examined by caspase 3/7 activity assay and western blotting of apoptotic associated proteins. Effects of H7N9/NS1on mitochondrial membrane potential were investigated by flow cytometry. Results: The expression of H7N9/NS1 in A549 cells activated caspase 3/7 and increased the protein levels of cleaved caspase 7 and cleaved poly (ADP-ribose) polymerase (PARP). H7N9/NS1-expressing A549 cells displayed a decrease in mitochondrial membrane potential. In addition, H7N9/NS1 increased the protein levels of total p53, p53 phosphorylated at Ser46 and Ser37, activated caspase 9, and the Bax/Bcl-2 ratio. Conclusion: Our results suggest that H7N9/NS1 protein causes the accumulation of p53 by increasing phosphorylation levels of p53 and the induction of mitochondrial dysfunction, which may contribute to H7N9/NS1-induced apoptosis in A549 cells.

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“…2E) which further cleaved full length PARP1 (116 kDa) to its inactive 89 kDa fragment (p89/p116; P <0.01 versus CON; Fig. 2E), thereby attenuating the DNA repair function of PARP1 [31]. MEL co-treatment resulted in inhibition of ATR-induced DNA fragmentation, as evident from suppression of the cleavage of caspase-3 (p17/p32; P <0.05 versus ATR) and PARP1 (p89/p116; P <0.05 versus ATR; Fig.…”

Section: Resultsmentioning

confidence: 97%

Melatonin Reverses Fas, E2F-1 and Endoplasmic Reticulum Stress Mediated Apoptosis and Dysregulation of Autophagy Induced by the Herbicide Atrazine in Murine Splenocytes

et al. 2014

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Exposure to the herbicide Atrazine (ATR) can cause immunotoxicity, apart from other adverse consequences for animal and human health. We aimed at elucidating the apoptotic mechanisms involved in immunotoxicity of ATR and their attenuation by Melatonin (MEL). Young Swiss mice were divided into control, ATR and MEL+ATR groups based on daily (x14) intraperitoneal administration of the vehicle (normal saline), ATR (100 mg/kg body weight) and MEL (20 mg/kg body weight) with ATR. Isolated splenocytes were processed for detection of apoptosis by Annexin V-FITC and TUNEL assays, and endoplasmic reticulum (ER) stress by immunostaining. Key proteins involved in apoptosis, ER stress and autophagy were quantified by immunoblotting. ATR treatment resulted in Fas-mediated activation of caspases 8 and 3 and inactivation of PARP1 which were inhibited significantly by co-treatment with MEL. MEL also attenuated the ATR-induced, p53 independent mitochondrial apoptosis through upregulation of E2F-1 and PUMA and suppression of their downstream target Bax. An excessive ER stress triggered by ATR through overexpression of ATF-6α, spliced XBP-1, CREB-2 and GADD153 signals was reversed by MEL. MEL also reversed the ATR-induced impairment of autophagy which was indicated by a decline in BECN-1, along with significant enhancement in LC3B-II and p62 expressions. Induction of mitochondrial apoptosis, ER stress and autophagy dysregulation provide a new insight into the mechanism of ATR immunotoxicity. The cytoprotective role of MEL, on the other hand, was defined by attenuation of ER stress, Fas-mediated and p53 independent mitochondria-mediated apoptosis as well as autophagy signals.

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The multikinase inhibitor Sorafenib displays significant antiproliferative effects and induces apoptosis via caspase 3, 7 and PARP in B- and T-lymphoblastic cells

Cited by 46 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

The Novel H7N9 Influenza A Virus NS1 Induces p53-Mediated Apoptosis of A549 Cells

Melatonin Reverses Fas, E2F-1 and Endoplasmic Reticulum Stress Mediated Apoptosis and Dysregulation of Autophagy Induced by the Herbicide Atrazine in Murine Splenocytes

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