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 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

Cathepsin L is involved in 6-hydroxydopamine induced apoptosis of SH-SY5Y neuroblastoma cells

2011 ◽  
Vol 1387 ◽  
pp. 29-38 ◽  
Author(s):  
Bei Xiang ◽  
Xifeng Fei ◽  
Wenzhuo Zhuang ◽  
Yun Fang ◽  
Zhenghong Qin ◽  
...  
Keyword(s):  
Cathepsin L ◽  
Neuroblastoma Cells ◽  
Induced Apoptosis ◽  
6 Hydroxydopamine

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 Сhanges in subcellular distribution of lysosomal cysteine proteinases activity in parenchymatous organs of rats under the action of nitric oxide synthesis modulators

2018 ◽  
Vol 5 (3) ◽  
pp. 28-39
Author(s):  
M. A. Fomina ◽  
A. A. Terent'ev
Keyword(s):  
Nitric Oxide ◽  
Subcellular Distribution ◽  
Cathepsin L ◽  
Kidney Tissue ◽  
Selective Inhibitor ◽  
No Synthase ◽  
Nitric Oxide Synthesis ◽  
Lysosomal Activity ◽  
Lysosomal Fraction ◽  
Cathepsin H

Aim. To study the effect of non-selective inhibitor of NO-synthase N-nitro-L-arginine methyl ester (L-NAME) and substrate of nitric oxide synthesis L-arginine on the activity of cathepsins B, L, H and its subcellular distribution in liver, kidney and lung tissues.Materials and methods. The object of study – male rats Wistar line, the material was the cytoplasmic and lysosomal fraction of homogenates of liver, kidney, lung tissues. A non-selective inhibitor of inducible NO-synthase N-nitro-L-arginine methyl ester (L-NAME) was applied at a dose of 25 mg/kg, the substrate of NO synthesis L-arginine – at a dose of 500 mg/kg. Activity of cathepsins B, L, H was defined separately in the cytoplasmic and lysosomal fractions by spectrofluorometry quantitative determination of the specific substrate cleavage product 7-amido-4-methylcoumarin.Results. Suppression of nitric oxide synthesis by non-selective inhibitor of NO-synthase L-NAME (25 mg/kg, 7 days) in the kidney tissue leads to a decrease in the activity of cathepsins В, L, H in lysosomal fraction with a parallel increase in non-lysosomal activity of cathepsin L, in the liver tissue leads to an increase in lysosomal activity of cathepsin H and a decrease in non-lysosomal activity of cathepsin L. The substrate of nitric oxide synthesis L-arginine (500 mg/kg, 10 days) only causes increased activity of cathepsin L in non-lysosomal fraction of liver tissue, leads to increased lysosomal activity of cathepsin H in kidney tissue, the lung tissue shows a significant increase in the activity of the all studied cathepsins in non-lysosomal fraction, accompanied by an increase in lysosomal activity of cathepsins B and H. The revealed changes are associated with the signs of changes in the ratio of pro-enzyme and active forms of cathepsins.Conclusion. The effects of non-selective inhibitor and substrate of nitric oxide synthesis on the total activity of cathepsins B, L and H in parenchymatous organs and its subcellular distribution are tissue-specific and multidirectional in some cases and are accompanied by signs of changes in the ratio of pro-enzyme and enzymatically active forms mainly due to an increase of pro-enzyme forms.

scholarly journals Calpain-Mediated Bid Cleavage and Calpain-Independent Bak Modulation: Two Separate Pathways in Cisplatin-Induced Apoptosis

2002 ◽  
Vol 22 (9) ◽  
pp. 3003-3013 ◽  
Author(s):  
Aleksandra Mandic ◽  
Kristina Viktorsson ◽  
Linda Strandberg ◽  
Thomas Heiden ◽  
Johan Hansson ◽  
...  
Keyword(s):  
Cathepsin L ◽  
Inhibitory Effect ◽  
Dominant Negative ◽  
Dominant Negative Mutant ◽  
Drug Induced ◽  
Calpain Activation ◽  
Isolated Mitochondria ◽  
Induced Apoptosis ◽  
Calpain Inhibitors

ABSTRACT Calpain is a ubiquitous protease with potential involvement in apoptosis. We report that in human melanoma cells, cisplatin-induced calpain activation occurs early in apoptosis. Calpain activation and subsequent apoptosis were inhibited by calpeptin and PD150606, two calpain inhibitors with different modes of action. Furthermore, cisplatin induced cleavage of the BH3-only protein Bid, yielding a 14-kDa fragment similar to proapoptotic, caspase-cleaved Bid. However, Bid cleavage was inhibited by inhibitors of calpain, but not by inhibitors of caspases or of cathepsin L. Recombinant Bid was cleaved in vitro by both recombinant calpain and by lysates of cisplatin-treated cells. Cleavage was calpeptin sensitive, and the cleavage site was mapped between Gly70 and Arg71. Calpain-cleaved Bid induced cytochrome c release from isolated mitochondria. While calpeptin did not affect cisplatin-induced modulation of Bak to its proapoptotic conformation, a dominant-negative mutant of MEKK1 (dnMEKK) inhibited Bak modulation. dnMEKK did not, however, block Bid cleavage. The combination of dnMEKK and calpeptin had an additive inhibitory effect on apoptosis. In summary, calpain-mediated Bid cleavage is important in drug-induced apoptosis, and cisplatin induces at least two separate apoptotic signaling pathways resulting in Bid cleavage and Bak modulation, respectively.

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.

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