Molecular mechanisms of mistletoe plant extract-induced apoptosis in acute lymphoblastic leukemia in vivo and in vitro

2008 ◽  
Vol 264 (2) ◽  
pp. 218-228 ◽  
Author(s):  
Georg Seifert ◽  
Patrick Jesse ◽  
Alfred Laengler ◽  
Tobias Reindl ◽  
Maria Lüth ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Plant Extract ◽  
Molecular Mechanisms ◽  
Lymphoblastic Leukemia ◽  
Induced Apoptosis

In vitro and in vivo correlation of cyclosporin A-induced apoptosis in acute lymphoblastic leukemia

2009 ◽  
Vol 63 (3) ◽  
pp. 207-209 ◽  
Author(s):  
O. Sezer ◽  
M. Schweigert ◽  
C. Naujokat ◽  
I. Mai ◽  
H-G. Mergenthaler ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Cyclosporin A ◽  
Lymphoblastic Leukemia ◽  
Induced Apoptosis

In vitro susceptibility to dexamethasone- and doxorubicin-induced apoptotic cell death in context of maturation stage, responsiveness to interleukin 7, and early cytoreduction in vivo in childhood T-cell acute lymphoblastic leukemia

Blood ◽  
2002 ◽  
Vol 99 (11) ◽  
pp. 4109-4115 ◽  
Author(s):  
Christian Wuchter ◽  
Velia Ruppert ◽  
Martin Schrappe ◽  
Bernd Dörken ◽  
Wolf-Dieter Ludwig ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Apoptotic Cell ◽  
Lymphoblastic Leukemia ◽  
Therapy Response ◽  
Drug Induced ◽  
In Vitro Susceptibility ◽  
Interleukin 7 ◽  
Induced Apoptosis

Within childhood T-cell acute lymphoblastic leukemia (T-ALL), patients with a cortical (CD1a+) immunophenotype have been identified as a subgroup with favorable outcome in the acute lymphoblastic leukemia–Berlin-Frankfurt-Münster (ALL-BFM), Cooperative study group for childhood acute lymphoblastic leukemia (COALL) and Pediatric Oncology Group studies. We investigated in leukemic samples of children with T-ALL (n = 81) whether the different in vivo therapy response could be linked to differential in vitro susceptibility to apoptotic cell death. The extent of dexamethasone- as well as doxorubicin-induced apoptosis, detected by annexin V staining, positively correlated with the expression levels of CD1a (Spearman correlation coefficient, rs = 0.3 and 0.4, respectively; P < .01). When compared to cortical T-ALL, mature (CD1a− , surface CD3+) T-ALL were significantly more resistant to doxorubicin, and immature, pro–/pre–T-ALL were more resistant to both drugs (P < .05). Apoptosis-related parameters (Bax, Bcl-2, CD95, and CD95-induced apoptosis) did not account for differential susceptibility to drug-induced apoptosis. By contrast, an interleukin 7–induced rescue of leukemic cells from spontaneous apoptosis, recently proposed to reflect distinct developmental stages and apoptotic programs in T-ALL, was highly associated with susceptibility to dexamethasone- but not doxorubicin-induced apoptosis (P < .001 versus P = .08). Analysis of clinical data showed that in vitro susceptibility to dexamethasone (but not to doxorubicin) closely correlated with early in vivo therapy response characterized by percentages of blast cells in bone marrow on day 15 (rs = −0.46, P = .001). Taken together, the in vitro assessment of drug-induced apoptosis revealed maturation-dependent differences within childhood T-ALL. The enhanced sensitivity to both drugs in cortical T-ALL might account for the better in vivo treatment response of this prognostically favorable T-ALL subgroup.

Interleukin-23 acts as antitumor agent on childhood B-acute lymphoblastic leukemia cells

Blood ◽  
2010 ◽  
Vol 116 (19) ◽  
pp. 3887-3898 ◽  
Author(s):  
Claudia Cocco ◽  
Sara Canale ◽  
Chiara Frasson ◽  
Emma Di Carlo ◽  
Emanuela Ognio ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Antitumor Activity ◽  
Molecular Mechanisms ◽  
Lymphoblastic Leukemia ◽  
Antitumor Agent ◽  
Underlying Mechanisms ◽  
Interleukin 23 ◽  
Novel Drug

Abstract Interleukin (IL)–23 is a proinflammatory cytokine belonging to the IL-12 superfamily. The antitumor activity of IL-23 is controversial, and it is unknown whether or not the cytokine can act directly on tumor cells. The aim of this study was to investigate the potential direct antitumor activity of IL-23 in pediatric B-acute lymphoblastic leukemia (B-ALL) cells and to unravel the molecular mechanisms involved. Here, we show, for the first time, that IL-23R is up-regulated in primary B-ALL cells, compared with normal early B lymphocytes, and that IL-23 dampens directly tumor growth in vitro and in vivo through the inhibition of tumor cell proliferation and induction of apoptosis. The latter finding is related to IL-23–induced up-regulation of miR15a expression and the consequent down-regulation of BCL-2 protein expression in pediatric B-ALL cells. This study demonstrates that IL-23 possesses antileukemic activity and unravels the underlying mechanisms. Thus, IL-23 may be a candidate novel drug for the treatment of B-ALL patients unresponsive to current therapeutic standards.

scholarly journals miR-101 Represses T-Cell Acute Lymphoblastic Leukemia by Targeting CXCR7/STAT3 Axis

2019 ◽  
Vol 27 (9) ◽  
pp. 997-1006 ◽  
Author(s):  
Xue-Yi Yang ◽  
Ye Sheng
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
T Cell ◽  
Molecular Mechanisms ◽  
Lymphoblastic Leukemia ◽  
Inhibitory Effects ◽  
Cell Acute Lymphoblastic Leukemia ◽  
Direct Target ◽  
Proliferation And Invasion

Although miR-101 is involved in the development and progression of T-cell acute lymphoblastic leukemia (T-ALL), the underlying molecular mechanisms remain unclear. In this article, we report that miR-101 expression was inversely correlated with CX chemokine receptor 7 (CXCR7) level in T-ALL. Introducing miR-101 inhibited T-ALL cell proliferation and invasion in vitro and suppressed tumor growth and lung metastasis in vivo. CXCR7 was identified as a direct target of miR-101. The inhibitory effects of miR-101 were mimicked and counteracted by CXCR7 depletion and overexpression, respectively. Mechanistically, miR-101 targets CXCR7/STAT3 axis to reduce T-ALL growth and metastasis. Overall, these findings implied the potential application of miR-101 and CXCR7 in T-ALL treatment.

scholarly journals BRD4 PROTAC degrader ARV-825 inhibits T-cell acute lymphoblastic leukemia by targeting 'Undruggable' Myc-pathway genes

2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Shuiyan Wu ◽  
You Jiang ◽  
Yi Hong ◽  
Xinran Chu ◽  
Zimu Zhang ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Cell Proliferation ◽  
Acute Lymphoblastic Leukemia ◽  
Caspase 3 ◽  
Lymphoblastic Leukemia ◽  
Rna Seq ◽  
Cell Acute Lymphoblastic Leukemia ◽  
Bet Protein

Abstract Background T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive disease with a high risk of induction failure and poor outcomes, with relapse due to drug resistance. Recent studies show that bromodomains and extra-terminal (BET) protein inhibitors are promising anti-cancer agents. ARV-825, comprising a BET inhibitor conjugated with cereblon ligand, was recently developed to attenuate the growth of multiple tumors in vitro and in vivo. However, the functional and molecular mechanisms of ARV-825 in T-ALL remain unclear. This study aimed to investigate the therapeutic efficacy and potential mechanism of ARV-825 in T-ALL. Methods Expression of the BRD4 were determined in pediatric T-ALL samples and differential gene expression after ARV-825 treatment was explored by RNA-seq and quantitative reverse transcription-polymerase chain reaction. T-ALL cell viability was measured by CCK8 assay after ARV-825 administration. Cell cycle was analyzed by propidium iodide (PI) staining and apoptosis was assessed by Annexin V/PI staining. BRD4, BRD3 and BRD2 proteins were detected by western blot in cells treated with ARV-825. The effect of ARV-825 on T-ALL cells was analyzed in vivo. The functional and molecular pathways involved in ARV-825 treatment of T-ALL were verified by western blot and chromatin immunoprecipitation (ChIP). Results BRD4 expression was higher in pediatric T-ALL samples compared with T-cells from healthy donors. High BRD4 expression indicated a poor outcome. ARV-825 suppressed cell proliferation in vitro by arresting the cell cycle and inducing apoptosis, with elevated poly-ADP ribose polymerase and cleaved caspase 3. BRD4, BRD3, and BRD2 were degraded in line with reduced cereblon expression in T-ALL cells. ARV-825 had a lower IC50 in T-ALL cells compared with JQ1, dBET1 and OTX015. ARV-825 perturbed the H3K27Ac-Myc pathway and reduced c-Myc protein levels in T-ALL cells according to RNA-seq and ChIP. In the T-ALL xenograft model, ARV-825 significantly reduced tumor growth and led to the dysregulation of Ki67 and cleaved caspase 3. Moreover, ARV-825 inhibited cell proliferation by depleting BET and c-Myc proteins in vitro and in vivo. Conclusions BRD4 indicates a poor prognosis in T-ALL. The BRD4 degrader ARV-825 can effectively suppress the proliferation and promote apoptosis of T-ALL cells via BET protein depletion and c-Myc inhibition, thus providing a new strategy for the treatment of T-ALL.

scholarly journals In vitro and in vivo single-agent efficacy of checkpoint kinase inhibition in acute lymphoblastic leukemia

2015 ◽  
Vol 8 (1) ◽  
Author(s):  
Ilaria Iacobucci ◽  
Andrea Ghelli Luserna Di Rorà ◽  
Maria Vittoria Verga Falzacappa ◽  
Claudio Agostinelli ◽  
Enrico Derenzini ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Lymphoblastic Leukemia ◽  
Single Agent ◽  
Kinase Inhibition ◽  
Checkpoint Kinase

scholarly journals Alantolactone inhibits cell autophagy and promotes apoptosis via AP2M1 in acute lymphoblastic leukemia

2020 ◽  
Vol 20 (1) ◽  
Author(s):  
Ce Shi ◽  
Wenjia Lan ◽  
Zhenkun Wang ◽  
Dongguang Yang ◽  
Jia Wei ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Tumor Growth ◽  
Cell Lines ◽  
Lymphoblastic Leukemia ◽  
Dependent Manner ◽  
Nude Mouse Model ◽  
Hematopoietic Malignancy ◽  
Induced Apoptosis ◽  
Anti Tumor Activity

Abstract Background Acute lymphoblastic leukemia (ALL) is an aggressive hematopoietic malignancy that is most commonly observed in children. Alantolactone (ALT) has been reported to exhibit anti-tumor activity in different types of cancer. The aim of the present study was to investigate the anti-tumor activity and molecular mechanism of ALT in ALL. Methods ALL cell lines were treated with 1, 5 and 10 μM ALT, and cell viability was assessed using an MTT assay and RNA sequencing. Flow cytometry, JC-1 staining and immunofluorescence staining assays were used to measure cell apoptosis and autophagy. Additionally, western blot analysis was used to detect expression of apoptosis and autophagy related proteins. Finally, the effects of ALT on tumor growth were assessed in a BV173 xenograft nude mouse model. Results ALT inhibited the proliferation of ALL cells in a dose-dependent manner. Additionally, it was demonstrated that ALT inhibited cell proliferation, colony formation, autophagy, induced apoptosis and reduced tumor growth in vivo through upregulating the expression of adaptor related protein complex 2 subunit mu 1 (AP2M1). Moreover, the autophagy activator rapamycin, attenuated the pro-apoptotic effects of ALT on BV173 and NALM6 cell lines. Overexpression of AP2M1 decreased the expression of Beclin1 and the LC3-II/LC3-1 ratio, and increased p62 expression. Knockdown of Beclin1 increased the levels of bax, cleaved caspase 3 and cytochrome C, and decreased bcl-2 expression. Conclusions The present study demonstrated that ALT exerts anti-tumor activity through inducing apoptosis and inhibiting autophagy by upregulating AP2M1 in ALL, highlighting a potential therapeutic strategy for treatment of ALL.

scholarly journals miR-22-3p Negatively Affects Tumor Progression in T-Cell Acute Lymphoblastic Leukemia

Cells ◽  
2020 ◽  
Vol 9 (7) ◽  
pp. 1726
Author(s):  
Valentina Saccomani ◽  
Angela Grassi ◽  
Erich Piovan ◽  
Deborah Bongiovanni ◽  
Ludovica Di Martino ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
T Cell ◽  
Target Genes ◽  
Cell Transformation ◽  
Lymphoblastic Leukemia ◽  
T Cell Development ◽  
Cell Acute Lymphoblastic Leukemia ◽  
Notch1 Signaling Pathway

T-cell acute lymphoblastic leukemia (T-ALL) is a rare, aggressive disease arising from T-cell precursors. NOTCH1 plays an important role both in T-cell development and leukemia progression, and more than 60% of human T-ALLs harbor mutations in components of the NOTCH1 signaling pathway, leading to deregulated cell growth and contributing to cell transformation. Besides multiple NOTCH1 target genes, microRNAs have also been shown to regulate T-ALL initiation and progression. Using an established mouse model of T-ALL induced by NOTCH1 activation, we identified several microRNAs downstream of NOTCH1 activation. In particular, we found that NOTCH1 inhibition can induce miR-22-3p in NOTCH1-dependent tumors and that this regulation is also conserved in human samples. Importantly, miR-22-3p overexpression in T-ALL cells can inhibit colony formation in vitro and leukemia progression in vivo. In addition, miR-22-3p was found to be downregulated in T-ALL specimens, both T-ALL cell lines and primary samples, relative to immature T-cells. Our results suggest that miR-22-3p is a functionally relevant microRNA in T-ALL whose modulation can be exploited for therapeutic purposes to inhibit T-ALL progression.

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