scholarly journals Survivin selective inhibitor YM155 promotes cisplatin-induced apoptosis in embryonal rhabdomyosarcoma

2016 ◽  
Vol 48 (5) ◽  
pp. 1847-1854 ◽  
Author(s):  
TAKEHISA UENO ◽  
SHUICHIRO UEHARA ◽  
KENGO NAKAHATA ◽  
HIROOMI OKUYAMA
Keyword(s):  
Selective Inhibitor ◽  
Embryonal Rhabdomyosarcoma ◽  
Induced Apoptosis

Hurpin Is a Selective Inhibitor of Lysosomal Cathepsin L and Protects Keratinocytes from Ultraviolet-Induced Apoptosis†

Biochemistry ◽  
2003 ◽  
Vol 42 (24) ◽  
pp. 7381-7389 ◽  
Author(s):  
Thomas Welss ◽  
Jiuru Sun ◽  
James A. Irving ◽  
Rainer Blum ◽  
A. Ian Smith ◽  
...  
Keyword(s):  
Cathepsin L ◽  
Selective Inhibitor ◽  
Induced Apoptosis

scholarly journals miR-21 Reduces Hydrogen Peroxide-Induced Apoptosis in c-kit+Cardiac Stem Cells In Vitro through PTEN/PI3K/Akt Signaling

2016 ◽  
Vol 2016 ◽  
pp. 1-14 ◽  
Author(s):  
Wenwen Deng ◽  
Yan Wang ◽  
Xianping Long ◽  
Ranzun Zhao ◽  
Zhenglong Wang ◽  
...  
Keyword(s):  
Hydrogen Peroxide ◽  
Stem Cells ◽  
Caspase 3 ◽  
Mrna Level ◽  
Cell Types ◽  
Akt Signaling ◽  
Selective Inhibitor ◽  
Cardiac Stem Cells ◽  
Induced Apoptosis

The low survival rate of cardiac stem cells (CSCs) in the infarcted myocardium hampers cell therapy for ischemic cardiomyopathy. MicroRNA-21 (miR-21) and one of its target proteins, PTEN, contribute to the survival and proliferation of many cell types, but their prosurvival effects in c-kit+CSC remain unclear. Thus, we hypothesized that miR-21 reduces hydrogen peroxide- (H2O2-) induced apoptosis in c-kit+CSC and estimated the contribution of PTEN/PI3K/Akt signaling to this oxidative circumstance. miR-21 mimics efficiently reduced H2O2-induced apoptosis in c-kit+CSC, as evidenced by the downregulation of the proapoptosis proteins caspase-3 and Bax and upregulation of the antiapoptotic Bcl-2. In addition, the gain of function of miR-21 in c-kit+CSC downregulated the protein level of PTEN although its mRNA level changed slightly; in the meantime, miR-21 overexpression also increased phospho-Akt (p-Akt). The antiapoptotic effects of miR-21 were comparable with Phen (bpV), the selective inhibitor of PTEN, while miR-21 inhibitor or PI3K’s inhibitor LY294002 efficiently attenuated the antiapoptotic effect of miR-21. Taken together, these results indicate that the anti-H2O2-induced apoptosis effect of miR-21 in c-kit+CSC is contributed by PTEN/PI3K/Akt signaling. miR-21 could be a potential molecule to facilitate the c-kit+CSC therapy in ischemic myocardium.

scholarly journals Combination of Venetoclax and CUDC-907 Shows Superior Antileukemic Activity Against Acute Myeloid Leukemia Ex Vivo

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 1571-1571
Author(s):  
Xinyu Li ◽  
Jun Ma ◽  
Yongwei Su ◽  
Jianyun Zhao ◽  
Holly Edwards ◽  
...  
Keyword(s):  
Dna Damage ◽  
Cell Lines ◽  
Myeloid Leukemia ◽  
Survival Rates ◽  
Selective Inhibitor ◽  
Antileukemic Activity ◽  
Dna Replication Stress ◽  
Induced Apoptosis ◽  
Overall Survival Rates ◽  
Acute Myeloid

Abstract Overall survival rates for adults and children with acute myeloid leukemia (AML) remain unacceptably low. Resistance to chemotherapy is the major factor contributing to such dismal overall survival rates. Chemoresistance in leukemia cell line models has been associated with overexpression of the anti-apoptotic Bcl-2 family members. As such, small molecule Bcl-2 inhibitors represent a promising strategy for treating AML. Venetoclax (ABT-199) is a Bcl-2-selective inhibitor that has demonstrated promising antileukemic activity against AML. However, initial resistance to ABT-199 remains a concern. In our most recent study, we identified a novel Mcl-1-mediated intrinsic mechanism of resistance to ABT-199 in AML cells: ABT-199 treatment results in increased sequestration of Bim by Mcl-1, preventing Bim from inducing apoptosis (Niu X, et al. Clinical Cancer Research. 2016; epub ahead of print). We also found that ABT-199 in combination with DNA damaging agents results in enhanced DNA damage and synergistic antileukemic activity against AML cells. Based on these findings, we hypothesized that simultaneously downregulating Mcl-1, upregulating Bim, and enhancing DNA replication stress and/or DNA damage would maximally enhance ABT-199-induced cell death, leading to potent synergistic antileukemic activity against AML. CUDC-907, a dual histone deacetylase inhibitor (HDACI) and PI3K inhibitor, is currently being tested in Phase I and Phase II clinical trials for the treatment of lymphoma, multiple myeloma, and advanced/relapsed solid tumors (www.clinicaltrials.gov). It inactivates both PI3K/AKT and MEK/ERK signaling pathways in different cancer cell types. Inhibition of these pathways has been shown to cause downregulation of Mcl-1 and upregulation of Bim and HDACIs have been demonstrated to downregulate CHK1 and Wee1, as well as upregulate Bim, leading to DNA damage and cell death. Furthermore, CHK1 and Wee1 inhibitors have been shown to cause DNA replication stress through downregulation of ribonucleotide reductase (RNR). Therefore, CUDC-907 would be an ideal compound to combine with ABT-199 to enhance its antileukemic activity against AML. In this study, we investigated the antileukemic activity of CUDC-907 alone and in combination with ABT-199 in both AML cell lines and primary patient samples. CUDC-907 treatment resulted in increased Bim expression and decreased Mcl-1, CHK-1, Wee1, and RRM1 (the regulatory subunit of RNR) expression in both AML cell lines and primary patient samples. Ectopic overexpression of Mcl-1 and shRNA knockdown of Bim demonstrated that both were at least partially involved in CUDC-907-induced apoptosis. Treatment with a CHK1-selective inhibitor LY2603618, the Wee1-selective inhibitor MK-1775, or hydroxyurea (RNR inhibitor) enhanced CUDC-907-induced apoptosis in a synergistic fashion, demonstrating that downregulation of Wee1, CHK1, and RRM1 was also an important contributor to CUDC-907-induced apoptosis. Consistent with our hypothesis, the combination of CUDC-907 and ABT-199 resulted in significantly increased apoptosis compared to single drug treatment and excellent synergy in both AML cell lines (n=6) and primary patient samples (n=18), regardless of their sensitivities to ABT-199. Synergy was also detected when AML cells were treated with CUDC-907 first for 16 h and then followed by ABT-199 treatment for another 8 h. Western blots revealed that combined treatment caused further decrease of Mcl-1, CHK1, and Wee1, while comet assays revealed that the combination caused significantly increased DNA strand breaks in both AML cell lines and primary patient samples. Our results demonstrate that CUDC-907 synergizes with ABT-199 in AML cells, and support the clinical development of the combination of CUDC-907 and ABT-199 in the treatment of AML. Disclosures Yang: Seattle Genetics: Research Funding.

BCL-2 selective inhibitor ABT-199 primes rhabdomyosarcoma cells to histone deacetylase inhibitor-induced apoptosis

Oncogene ◽  
2018 ◽  
Vol 37 (39) ◽  
pp. 5325-5339 ◽  
Author(s):  
Ulrike Heinicke ◽  
Tinka Haydn ◽  
Sarah Kehr ◽  
Meike Vogler ◽  
Simone Fulda
Keyword(s):  
Histone Deacetylase ◽  
Histone Deacetylase Inhibitor ◽  
Selective Inhibitor ◽  
Deacetylase Inhibitor ◽  
Induced Apoptosis

Absence of temporal ordering of apoptotic features in heat-shock treated leukemia and lymphoma cell lines

1996 ◽  
Vol 54 ◽  
pp. 758-759
Author(s):  
D. W. Fairbain ◽  
M.D. Standing ◽  
K.L. O'Neill
Keyword(s):  
Heat Shock ◽  
Cell Lines ◽  
Chromatin Condensation ◽  
Membrane Integrity ◽  
Resistant Cell ◽  
Membrane Blebbing ◽  
Late Loss ◽  
Induced Apoptosis ◽  
Dying Cells ◽  
In Cells

Apoptosis is a genetically defined response to physiological stimuli that results in cellular suicide. Features common to apoptotic cells include chromatin condensation, oligonucleosomal DNA fragmentation, membrane blebbing, nuclear destruction, and late loss of ability to exclude vital dyes. These characteristics contrast markedly from pathological necrosis, in which membrane integrity loss is demonstrated early, and other features of apoptosis, which allow a non-inflammatory removal of dead and dying cells, are absent. Using heat shock-induced apoptosis as a model for examining stress response in cells, we undertook to categorize a variety of human leukemias and lymphomas with regard to their response to heat shock. We were also interested in determining whether a common temporal order was followed in cells dying by apoptosis. In addition, based on our previous results, we investigated whether increasing heat load resulted in increased apoptosis, with particular interest in relatively resistant cell lines, or whether the mode of death changed from apoptosis to necrosis.

Gene array and knockout mouse analysis of VP-16 induced apoptosis in the murine small intestine

2001 ◽  
Vol 120 (5) ◽  
pp. A660-A660
Author(s):  
D MCMICHAEL ◽  
A DAVIES ◽  
E MARSHMAN ◽  
P OTTEWELL ◽  
J JENKINS ◽  
...  
Keyword(s):  
Small Intestine ◽  
Knockout Mouse ◽  
Gene Array ◽  
Murine Small Intestine ◽  
Induced Apoptosis

672: Regulation of Cavernous Nerve Injury-Induced Apoptosis by Sonic Hedgehog

2007 ◽  
Vol 177 (4S) ◽  
pp. 225-225
Author(s):  
Carol A. Podlasek ◽  
Yi Tang ◽  
Cynthia L. Meraz ◽  
Kevin E. McKenna ◽  
Kevin T. McVary
Keyword(s):  
Nerve Injury ◽  
Sonic Hedgehog ◽  
Cavernous Nerve ◽  
Induced Apoptosis ◽  
Cavernous Nerve Injury
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