scholarly journals CDK7 Inhibitor THZ1 Induces the Cell Apoptosis of B-Cell Acute Lymphocytic Leukemia by Perturbing Cellular Metabolism

2021 ◽  
Vol 11 ◽  
Author(s):  
Tuersunayi Abudureheman ◽  
Jing Xia ◽  
Ming-Hao Li ◽  
Hang Zhou ◽  
Wei-Wei Zheng ◽  
...  
Keyword(s):  
B Cell ◽  
Cell Apoptosis ◽  
Acute Lymphocytic Leukemia ◽  
Cellular Metabolism ◽  
Underlying Mechanism ◽  
Inhibitory Effect ◽  
Lymphocytic Leukemia ◽  
High Concentration ◽  
P53 Expression

B-cell acute lymphocytic leukemia (B-ALL) is a malignant blood cancer that develops in children and adults and leads to high mortality. THZ1, a covalent cyclin-dependent kinase 7 (CDK7) inhibitor, shows anti-tumor effects in various cancers by inhibiting cell proliferation and inducing apoptosis. However, whether THZ1 has an inhibitory effect on B-ALL cells and the underlying mechanism remains obscure. In this study, we showed that THZ1 arrested the cell cycle of B-ALL cells in vitro in a low concentration, while inducing the apoptosis of B-ALL cells in vitro in a high concentration by activating the apoptotic pathways. In addition, RNA-SEQ results revealed that THZ1 disrupted the cellular metabolic pathways of B-ALL cells. Moreover, THZ1 suppressed the cellular metabolism and blocked the production of cellular metabolic intermediates in B-ALL cells. Mechanistically, THZ1 inhibited the cellular metabolism of B-ALL by downregulating the expression of c-MYC-mediated metabolic enzymes. However, THZ1 treatment enhanced cell apoptosis in over-expressed c-MYC B-ALL cells, which was involved in the upregulation of p53 expression. Collectively, our data demonstrated that CDK7 inhibitor THZ1 induced the apoptosis of B-ALL cells by perturbing c-MYC-mediated cellular metabolism, thereby providing a novel treatment option for B-ALL.

scholarly journals PIM Inhibitor SMI-4a Induces Cell Apoptosis and Cell Cycle Arrest in B-Cell Acute Lymphocytic Leukemia Cells Via the JAK2/STAT3 Pathway

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 4083-4083 ◽  
Author(s):  
Xingyi Kuang ◽  
Jie Xiong ◽  
Weili Wang ◽  
Xinyao Li ◽  
Tingting Lu ◽  
...  
Keyword(s):  
Cell Cycle ◽  
B Cell ◽  
Cell Cycle Arrest ◽  
Cell Apoptosis ◽  
Acute Lymphocytic Leukemia ◽  
Lymphocytic Leukemia ◽  
Stat3 Pathway ◽  
Cycle Arrest ◽  
Molecule Inhibitor

Abstract The serine/threonine PIM protein kinases are critical regulators of turmorigenesis in mutiple hematologic malignancies and solid cancers. We used real-time PCR to detect the expression of PIM in B-cell acute lymphocytic leukemia (B-ALL) patients, and found the expression of PIM in B-ALL patients was significantly higher than that in normal controls. SMI-4a is a pan-PIM small molecule inhibitor, and this agent exhibits demonstrable preclinical antitumour activity in a wide range of hematologic malignant cell lines. To further explore the effect of SMI-4a on B-ALL cells, B-ALL cell lines CCRF-SB and Sup-B15 were treated with this small molecule inhibitor, and the results showed that SMI-4a inhibited B-ALL cell proliferation in a dose- and time-dependent manner. Moreover, SMI-4a significantly promoted B-ALL cell apoptosis and caused cell cycle arrest in the G0/G1 phase. The results of Western blot showed that SMI-4a increased the expression of Caspase-3, Caspase-9, Bax and P21, and decreased the expression of Bcl-2 and CDK4. Furthermore, we found that SMI-4a significantly inhibits the activation of the JAK2/STAT3 pathway and HO-1 interferes with the JAK2/STAT3 pathway to inhibit SMI-4a-induced ALL cell apoptosis. Finally, xenograft experiments in NOD/SCID mice were operated to investigate the potential role of SMI-4a in B-ALL tumorigenesis in vivo. To observe the effect of SMI-4a on tumor growth in vivo, NOD/SCID mice were transplanted with B-ALL devied cells, and the tumor-bearing mice were intraperitoneally injected with saline and SMI-4a, respectively. As a result, tretment with SMI-4a resulted in a significant inhibition on tumor growth. In addition, PIM inhibtor obviously reduced the volume and weight of B-ALL cell-derived tumors. TUNEL assay revealed the proportion of apoptotic cells was higher in the SMI-4a-treated group than in the control group. Taken together, our data showed PIM inhibitor (SMI-4a) significantly inhibits the growth of B-ALL cells in vitro and in vivo and promotes apoptosis and cell cycle arrest. This suppressive effect is mediated partly through inhibiting the JAK2/STAT3 pathway activation. Disclosures No relevant conflicts of interest to declare.

scholarly journals CDK9 Inhibitor Induces the Apoptosis of B-Cell Acute Lymphocytic Leukemia by Inhibiting c-Myc-Mediated Glycolytic Metabolism

2021 ◽  
Vol 9 ◽  
Author(s):  
Wen-Li Huang ◽  
Tuersunayi Abudureheman ◽  
Jing Xia ◽  
Lei Chu ◽  
Hang Zhou ◽  
...  
Keyword(s):  
B Cell ◽  
Acute Lymphocytic Leukemia ◽  
Glucose Transporter ◽  
Lymphoblastic Leukemia ◽  
Lymphocytic Leukemia ◽  
Glycolytic Metabolism ◽  
Underlying Mechanisms ◽  
Apoptotic Pathways ◽  
Induced Apoptosis

B-cell acute lymphocytic leukemia (B-ALL), a common blood cancer in children, leads to high mortality. Cyclin-dependent kinase 9 inhibitor (CDK9i) effectively attenuates acute myeloid leukemia and chronic lymphoblastic leukemia by inducing apoptosis and inhibiting cell proliferation. However, the effect of CDK9i on B-ALL cells and the underlying mechanisms remain unclear. In this study, we showed that CDK9i induced the apoptosis of B-ALL cells in vitro by activating the apoptotic pathways. In addition, CDK9i restrained the glycolytic metabolism of B-ALL cells, and CDK9i-induced apoptosis was enhanced by co-treatment with glycolysis inhibitors. Furthermore, CDK9i restained the glycolysis of B-ALL cell lines by markedly downregulating the expression of glucose transporter type 1 (GLUT1) and the key rate-limiting enzymes of glycolysis, such as hexokinase 2 (HK2) and lactate dehydrogenase A (LDHA). Moreover, cell apoptosis was rescued in B-ALL cells with over-expressed c-Myc after treatment with CDK9i, which is involved in the enhancement of glycolytic metabolism. In summary, our findings suggest that CDK9 inhibitors induce the apoptosis of B-ALL cells by inhibiting c-Myc-mediated glycolytic metabolism, thus providing a new strategy for the treatment of B-ALL.

Scutellaria Baicalensis, a Herbal Medicine: Antitumor Activity Against Acute Lymphocytic Leukemia, Lymphoma and Myeloma in Vitro.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 4491-4491
Author(s):  
Takashi Kumagai ◽  
Claudia Muller ◽  
Julian C. Desmond ◽  
Yasufumi Imai ◽  
David Heber ◽  
...  
Keyword(s):  
Herbal Medicine ◽  
Cell Lines ◽  
Dose Response ◽  
Acute Lymphocytic Leukemia ◽  
Hematological Malignancies ◽  
Lymphocytic Leukemia ◽  
Scutellaria Baicalensis ◽  
Dependent Manner ◽  
P53 Expression

Abstract Scutellaria baicalensis is a widely used Chinese herbal medicine for anti-inflammatory and anti-cancer therapy. The anticancer activity of Scutellaria baicalensis against prostate, breast, hepatocellular, colon and squamous cell carcinomas in vitro has been reported. In this study, we initially investigated its in vitro antitumor activities against 29 cancer cell lines including prostate, breast, ovarian, endometrial and pancreatic cancers as well as myeloid and lymphocytic leukemias, lymphomas, myelomas. The cells were cultured with Scutellaria baicalensis at a dose of 50 μg/ml for 4 days. The herb showed strong anti-proliferative activities against Blin-1 and Nalm-6 acute lymphocytic leukemia cells, Daudi Burkitt′s lymphoma cells and NCI-H929 myeloma cells as measured by MTT assays. Dose-response studies showed an ED50 of 8.32 μg/ml (Blin-1), 12.3 μg/ml (Nalm-6), 4.57 μg/ml (Daudi) and 5.01 μg/ml (NCI-H929) as measured by soft agar colony assay. Treatment with Scutellaria bacalensis at 50 μg/ml for 2 days induced apoptosis of 30% of Blin-1, 17% of Nalm-6, 20% of Daudi and 39% of NCI-H929 cells as measured by Annexin V assay. It also induced G2/M cell cycle arrest of Daudi cells. Scutellaria baicalensis also induced mitchondrial damage in 4 cell lines as measured by fluorescent emissions using the JC-1 assay. Protein expressions were examined by western blot using Blin-1 cells that were most sensitive to Scutellaria baicalensis. After treatment with 50 μg/ml of Scutellaria baicalensis for 2 days, levels of p27KIP1 increased by 152 % independently of p53, expression of the pro-apoptotic gene Bax increased by 208 %, and the anti-apoptotic proteins Bcl-2 and Bcl-XL decreased by 64 % and 38 %, respectively. Notably Scutellaria baicalensis decreased the expression of c-myc oncogene in a dose-dependent manner (80 % decrease at 50 μg/ml). Scutellaria baicalensis contains 21% of baicalin as measured by HPLC. The antiproliferative dose-response assays were repeated using baicalin and calculating the percent baicalin in the herb showed that the results nearly mirrored those of Scutellaria baicalensis, suggesting baicalin is the major anticancer component of this herb. We conclude that Scutellaria baicalensis inhibited the cell growth of B cell hematological malignancies including ALL, lymphoma, and myeloma in vitro by induction of apoptosis associated with mitchondrial damage and modulation of the Bcl family of genes. Thus, Scutellaria baicalensis and its major component, baicalin, should be tested in clinical trials for these hematological malignancies.

PIM inhibitor SMI-4a induces cell apoptosis in B-cell acute lymphocytic leukemia cells via the HO-1-mediated JAK2/STAT3 pathway

Life Sciences ◽  
2019 ◽  
Vol 219 ◽  
pp. 248-256 ◽  
Author(s):  
Xingyi Kuang ◽  
Jie Xiong ◽  
Weili Wang ◽  
Xinyao Li ◽  
Tingting Lu ◽  
...  
Keyword(s):  
B Cell ◽  
Cell Apoptosis ◽  
Acute Lymphocytic Leukemia ◽  
Lymphocytic Leukemia ◽  
Leukemia Cells ◽  
Stat3 Pathway

In vitro drug resistance in B cell chronic lymphocytic leukemia: a comparison with acute myelocytic and acute lymphocytic leukemia

2005 ◽  
Vol 16 (3) ◽  
pp. 277-283 ◽  
Author(s):  
Anna ??leskog ◽  
Rolf Larsson ◽  
Martin H??glund ◽  
J??rgen Kristensen ◽  
Peter Nygren ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Chronic Lymphocytic Leukemia ◽  
B Cell ◽  
Acute Lymphocytic Leukemia ◽  
Lymphocytic Leukemia ◽  
Cell Chronic Lymphocytic Leukemia

scholarly journals Integrin α6 mediates the drug resistance of acute lymphoblastic B-cell leukemia

Blood ◽  
2020 ◽  
Vol 136 (2) ◽  
pp. 210-223 ◽  
Author(s):  
Eun Ji Gang ◽  
Hye Na Kim ◽  
Yao-Te Hsieh ◽  
Yongsheng Ruan ◽  
Heather A. Ogana ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Tyrosine Kinase ◽  
B Cell ◽  
Kinase Inhibitor ◽  
Residual Disease ◽  
Lymphoblastic Leukemia ◽  
Underlying Mechanism ◽  
Conditional Knockout

Abstract Resistance to multimodal chemotherapy continues to limit the prognosis of acute lymphoblastic leukemia (ALL). This occurs in part through a process called adhesion-mediated drug resistance, which depends on ALL cell adhesion to the stroma through adhesion molecules, including integrins. Integrin α6 has been implicated in minimal residual disease in ALL and in the migration of ALL cells to the central nervous system. However, it has not been evaluated in the context of chemotherapeutic resistance. Here, we show that the anti-human α6-blocking Ab P5G10 induces apoptosis in primary ALL cells in vitro and sensitizes primary ALL cells to chemotherapy or tyrosine kinase inhibition in vitro and in vivo. We further analyzed the underlying mechanism of α6-associated apoptosis using a conditional knockout model of α6 in murine BCR-ABL1+ B-cell ALL cells and showed that α6-deficient ALL cells underwent apoptosis. In vivo deletion of α6 in combination with tyrosine kinase inhibitor (TKI) treatment was more effective in eradicating ALL than treatment with a TKI (nilotinib) alone. Proteomic analysis revealed that α6 deletion in murine ALL was associated with changes in Src signaling, including the upregulation of phosphorylated Lyn (pTyr507) and Fyn (pTyr530). Thus, our data support α6 as a novel therapeutic target for ALL.

scholarly journals Spleen Tyrosine Kinase Inhibition Modulates p53 Activity

2017 ◽  
Vol 10 ◽  
pp. 117906601773156 ◽  
Author(s):  
Mohammad Althubiti
Keyword(s):  
Tyrosine Kinase ◽  
Survival Rates ◽  
Lymphocytic Leukemia ◽  
Spleen Tyrosine Kinase ◽  
Ht1080 Cell ◽  
P53 Expression ◽  
Chemical Inhibitors ◽  
Dependent Mechanism

Spleen tyrosine kinase (SYK) is a cytoplasmic enzyme that promotes survival and proliferation of B cells. SYK inhibition has shown promising results in the treatment of arthritis and chronic lymphocytic leukemia (CLL). However, in other context, it has been shown that SYK overexpression in epithelial cancer cells induced senescence in p53-dependent mechanism, which underscored its antineoplastic activity in vitro. Here, we show that SYK was induced in response of DNA damage in parallel with p53 levels. In addition, using chemical inhibitors of SYK reduced p53 levels in HCT116 and HT1080 cell lines, which underlines the role of SYK inhibition on p53 activity. Furthermore, SYK inhibition modulated the cell growth, which resulted in a decreasing in cell death. Interestingly, SYK expression showed a positive prognosis in patients with solid tumors in correlations with their survival rates, as expected negative correlation was seen between SYK expression and survival rate of patients with CLL. In conclusion, these findings demonstrate that SYK inhibition modulates p53 expression and activity in HCT116 and HT1080 cells. Reconsidering using of SYK inhibitors in clinical setting in the future should be evaluated carefully in accordance with these findings to prevent the formation of secondary malignancies.

scholarly journals Influence of cytotoxicity enhancers in combination with human serum on the activity of CD22-recombinant ricin A against B cell lines, chronic and acute lymphocytic leukemia cells

Leukemia ◽  
1999 ◽  
Vol 13 (2) ◽  
pp. 241-249 ◽  
Author(s):  
PJ van Horssen ◽  
YVJM van Oosterhout ◽  
S Evers ◽  
HHJ Backus ◽  
MGCT van Oijen ◽  
...  
Keyword(s):  
B Cell ◽  
Human Serum ◽  
Cell Lines ◽  
Acute Lymphocytic Leukemia ◽  
Lymphocytic Leukemia ◽  
Leukemia Cells ◽  
Ricin A

Evaluation of vecabrutinib as a model for non-covalent BTK/ITK inhibition for treatment of chronic lymphocytic leukemia

Blood ◽  
2021 ◽  
Author(s):  
Billy Michael Chelliah Jebaraj ◽  
Annika Müller ◽  
Rashmi Priyadharshini Dheenadayalan ◽  
Sascha Endres ◽  
Philipp M. Roessner ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Chronic Lymphocytic Leukemia ◽  
Inhibitory Effect ◽  
Lymphocytic Leukemia ◽  
Transfer Model ◽  
Treatment Benefit ◽  
Btk Inhibitors

Covalent Bruton tyrosine kinase (BTK) inhibitors such as ibrutinib have proven to be highly beneficial in the treatment of chronic lymphocytic leukemia (CLL). Interestingly, the off-target inhibition of IL-2-inducible T-cell kinase (ITK) by ibrutinib may also play a role in modulating the tumor microenvironment, potentially enhancing the treatment benefit. However, resistance to covalently binding BTK inhibitors can develop by a mutation in cysteine 481 of BTK (C481S), which prevents the irreversible binding of the drugs. In the present study we performed pre-clinical characterization of vecabrutinib, a next generation non-covalent BTK inhibitor, with ITK inhibitory properties similar to those of ibrutinib. Unlike ibrutinib and other covalent BTK inhibitors, vecabrutinib showed retention of the inhibitory effect on C481S BTK mutants in vitro, similar to that of wildtype BTK. In the murine Eµ-TCL1 adoptive transfer model, vecabrutinib reduced tumor burden and significantly improved survival. Vecabrutinib treatment led to a decrease in CD8+ effector and memory T-cell populations, while the naïve populations were increased. Of importance, vecabrutinib treatment significantly reduced frequency of regulatory CD4+ T-cells (Tregs) in vivo. Unlike ibrutinib, vecabrutinib treatment showed minimal adverse impact on activation and proliferation of isolated T-cells. Lastly, combination treatment of vecabrutinib with venetoclax was found to augment treatment efficacy, significantly improve survival and lead to favourable reprogramming of the microenvironment in the murine Eµ-TCL1 model. Thus, non-covalent BTK/ITK inhibitors such as vecabrutinib may be efficacious in C481S BTK mutant CLL, while preserving the T-cell immunomodulatory function of ibrutinib.

Chronic lymphocytic leukemia: revelations from the B-cell receptor

Blood ◽  
2004 ◽  
Vol 103 (12) ◽  
pp. 4389-4395 ◽  
Author(s):  
Freda K. Stevenson ◽  
Federico Caligaris-Cappio
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
B Cell ◽  
Cell Receptor ◽  
B Cell Receptor ◽  
Lymphocytic Leukemia ◽  
Cell Of Origin ◽  
Regulatory B Cell ◽  
V Genes

Abstract The finding that chronic lymphocytic leukemia (CLL) consists of 2 clinical subsets, distinguished by the incidence of somatic mutations in the immunoglobulin (Ig) variable region (V) genes, has clearly linked prognosis to biology. Antigen encounter by the cell of origin is indicated in both subsets by selective but distinct expression of V genes, with evidence for continuing stimulation after transformation. The key to distinctive tumor behavior likely relates to the differential ability of the B-cell receptor (BCR) to respond. Both subsets may be undergoing low-level signaling in vivo, although analysis of blood cells limits knowledge of critical events in the tissue microenvironment. Analysis of signal competence in vitro reveals that unmutated CLL generally continues to respond, whereas mutated CLL is anergized. Differential responsiveness may reflect the increased ability of post-germinal center B cells to be triggered by antigen, leading to long-term anergy. This could minimize cell division in mutated CLL and account for prognostic differences. Unifying features of CLL include low responsiveness, expression of CD25, and production of immunosuppressive cytokines. These properties are reminiscent of regulatory T cells and suggest that the cell of origin of CLL might be a regulatory B cell. Continuing regulatory activity, mediated via autoantigen, could suppress Ig production and lead to disease-associated hypogammaglobulinemia. (Blood. 2004;103:4389-4395)

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