Refine Search

New Search

Results: 23

(searched for: doi:10.3816/clml.2011.n.002)
Save to Scifeed
Page of 1
Articles per Page
by
Show export options
  Select all
Nan Jiang, Xinzhuo Zhang, Dalian Qin, Jing Yang, Anguo Wu, Long Wang, Yueshan Sun, Hong Li, Xin Shen, Jing Lin, et al.
Published: 23 February 2021
Frontiers in Genetics, Volume 12; doi:10.3389/fgene.2021.608017

Abstract:
Background Hepatocellular carcinoma (HCC) is one of the most leading causes of cancer death with a poor prognosis. However, the underlying molecular mechanisms are largely unclear, and effective treatment for it is limited. Using an integrated bioinformatics method, the present study aimed to identify the key candidate prognostic genes that are involved in HCC development and identify small-molecule drugs with treatment potential. Methods and Results In this study, by using three expression profile datasets from Gene Expression Omnibus database, 1,704 differentially expressed genes were identified, including 671 upregulated and 1,033 downregulated genes. Then, weighted co-expression network analysis revealed nine modules are related with pathological stage; turquoise module was the most associated module. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes pathway analyses (KEGG) indicated that these genes were enriched in cell division, cell cycle, and metabolic related pathways. Furthermore, by analyzing the turquoise module, 22 genes were identified as hub genes. Based on HCC data from gene expression profiling interactive analysis (GEPIA) database, nine genes associated with progression and prognosis of HCC were screened, including ANLN, BIRC5, BUB1B, CDC20, CDCA5, CDK1, NCAPG, NEK2, and TOP2A. According to the Human Protein Atlas and the Oncomine database, these genes were highly upregulated in HCC tumor samples. Moreover, multivariate Cox regression analysis showed that the risk score based on the gene expression signature of these nine genes was an independent prognostic factor for overall survival and disease-free survival in HCC patients. In addition, the candidate small-molecule drugs for HCC were identified by the CMap database. Conclusion In conclusion, the nine key gene signatures related to HCC progression and prognosis were identified and validated. The cell cycle pathway was the core pathway enriched with these key genes. Moreover, several candidate molecule drugs were identified, providing insights into novel therapeutic approaches for HCC.
Yue Shen, Chenxing Ji, Xuemin Jian, Juan Zhou, Qilin Zhang, Nidan Qiao, Yichao Zhang, Xuefei Shou, ,
Published: 18 January 2021
Frontiers in Endocrinology, Volume 11; doi:10.3389/fendo.2020.601984

Abstract:
PurposeTo investigate the role of heat-shock protein Hsp90 in adrenocorticotropic hormone (ACTH)-secreting cells, and to explore the potential clinical application of an inhibitor of Hsp90, 17-N-allylamino-17-demethoxygeldanamycin(17-AAG) in corticotropinomas [also known as “Cushing’s disease” (CD)].MethodsCulture of mouse pituitary tumor [AtT-20/D16v-F2 (ATCC® CRL-1795™)] cells and human pituitary ACTH-secreting tumor cells were employed. Hepatocellular carcinoma cell line (HLE) was used to evaluate EGFR inhibition by 17-AAG. Cell viability was evaluated using a commercial kit. The ACTH level was measured by a radioimmunoassay. Reverse transcription quantitative polymerase chain reaction (RT-qPCR) was used to measure expression of proopiomelanocortin (POMC) mRNA. Western blotting was done to measure protein levels.Results17-AAG suppressed the viability and proliferation, and promoted the apoptosis, of AtT-20/D16v-F2 cells. 17-AAG suppressed the synthesis and secretion of ACTH in AtT-20/D16v-F2 cells and down-regulated POMC transcription. 17-AAG acted in a similar pattern upon treatment with human pituitary ACTH-secreting tumor cells. Inhibition by 17-AAG was stronger in human pituitary ACTH-secreting tumor cells carrying the ubiquitin-specific protease-8 (USP8) mutant in comparison with cells carrying wild-type USP8.ConclusionsThe HSP90 inhibitor 17-AAG reduced the viability and secretory function of human pituitary ACTH-secreting tumor cells, and tumor cells carrying the USP8 mutant were more sensitive to 17-AAG than tumor cells carrying wild-type USP8. 17-AAG could be a potential treatment option for CD.
Jian Yang, Bei Wang, Yuankang Zhang, Shuqing Zhang, Shuai He, Zhi-Chuan Shi,
Organic & Biomolecular Chemistry, Volume 19, pp 988-992; doi:10.1039/d0ob02514c

The publisher has not yet granted permission to display this abstract.
Audrey E. Yñigez-Gutierrez,
Journal of Medicinal Chemistry, Volume 62, pp 8412-8428; doi:10.1021/acs.jmedchem.9b00246

The publisher has not yet granted permission to display this abstract.
Molecular Medicine, Volume 25; doi:10.1186/s10020-019-0079-0

Abstract:
Endometrial carcinoma represents one of the most common cancer types of the female reproductive tract. If diagnosed at an early stage, the 5-year survival rate is promising. However, recurrence and chemoresistance remain problematic for at least 15% of the patients. In the present study, we aim to reveal the mechanism by which PGK1 regulates chemoresistance in endometrial carcinoma. qPCR was performed to detect expression of PGK1 in clinical tissue samples of endometrial carcinoma. Specific shRNAs were employed to knockdown PGK1 expression in endometrial cancer cell lines. MTT assay was used to evaluate cell viability and cisplatin sensitivity of endometrial carcinoma cell lines. Western blot was performed to assess the effects of PGK1 knockdown on the expression levels of HSP90, DNA repair-associated proteins (c-JUN, FOSL1, and POLD1), and DNA methylation-related enzymes (DNMT1, DNMT3A and DNMT3B). Immunoprecipitation was performed to verify direct binding between PGK1 and HSP90. We first showed that PGK1 expression is elevated in tumor tissues of endometrial cancer, and high PGK1 levels are associated with clinical stages and metastasis. Knockdown of PGK1 inhibits proliferation of endometrial cancer cells, and enhances the inhibitory effect of cisplatin on cell viability. In addition, knockdown of PGK1 down-regulates the expression of DNA repair-related proteins, methylation-related enzymes, and total cellular methylation level. PGK1 was next shown to interact directly with HSP90 and exhibit pro-tumor effects by modulating the ATPase activity of HSP90. We propose that PGK1 mediates DNA repair and methylation through the HSP90/ERK pathway, and eventually enhances the chemoresistance to cisplatin. The results provide new insights on functions of PGK1 and HSP90, which might make them as promising targets for endometrial cancer chemotherapy.
, Konstantinos Evangelou, , Tomer Cooks, Theodoros P. Vassilakopoulos, Gerassimos A. Pangalis, Myrsini Kouloukoussa, Christos Kittas, ,
Published: 1 January 2019
Pharmacology & Therapeutics, Volume 193, pp 31-49; doi:10.1016/j.pharmthera.2018.08.006

Abstract:
Cellular senescence is a stress response mechanism ensuring homeostasis. Its temporal activation during embryonic development or normal adult life is linked with beneficial properties. In contrast, persistent (chronic) senescence seems to exert detrimental effects fostering aging and age-related disorders, such as cancer. Due to the lack of a reliable marker able to detect senescence in vivo, its precise impact in age-related diseases is to a large extent still undetermined. A novel reagent termed GL13 (SenTraGorTM) that we developed, allowing senescence recognition in any type of biological material, emerges as a powerful tool to study the phenomenon of senescence in vivo. Exploiting the advantages of this novel methodological approach, scientists will be able to detect and connect senescence with aggressive behavior in human malignancies, such as tolerance to chemotherapy in classical Hodgkin Lymphoma and Langerhans Cell Histiocytosis. The latter depicts the importance of developing the new and rapidly expanding field of senotherapeutic agents targeting and driving to cell death senescent cells. We discuss in detail the current progress of this exciting area of senotherapeutics and suggest its future perspectives and applications.
Qijun Wang, Bo Wang, Hao Deng, Yu Shangguan, Yan Lin, Yaqi Zhang, Zheming Zhang, , ,
The Journal of Organic Chemistry, Volume 84, pp 1006-1014; doi:10.1021/acs.joc.8b02997

The publisher has not yet granted permission to display this abstract.
Jun Dong, Zeyu Wu, Dan Wang, , Joel B. Nelson, ,
Molecular Cancer Therapeutics, Volume 18, pp 39-50; doi:10.1158/1535-7163.mct-18-0432

The publisher has not yet granted permission to display this abstract.
Published: 30 May 2018
Marine Drugs, Volume 16; doi:10.3390/md16060189

Abstract:
Chemical investigations on the fermentation extract obtained from an ascidian-derived Streptomyces sp. (USC-16018) yielded a new ansamycin polyketide, herbimycin G (1), as well as a known macrocyclic polyketide, elaiophylin (2), and four known diketopiperazines (3–6). The structures of the compounds were elucidated based on 1D/2D NMR and MS data. The absolute configuration of 1 was established by comparison of experimental and predicted electronic circular dichroism (ECD) data. Antiplasmodial activities were tested for the natural products against chloroquine sensitive (3D7) and chloroquine resistant (Dd2) Plasmodium falciparum strains; the two polyketides (1–2) demonstrated an inhibition of >75% against both parasite strains and while 2 was highly cytotoxic, herbimycin G (1) showed no cytotoxicity and good predicted water solubility.
Murugesan Velayutham, Arturo J. Cardounel, Zhenguo Liu,
Published: 6 April 2018
Frontiers in Oncology, Volume 8; doi:10.3389/fonc.2018.00097

Abstract:
Heat-shock factor-1 (HSF-1) is an important transcription factor that regulates pathogenesis of many human diseases through its extensive transcriptional regulation. Especially, it shows pleiotropic effects in human cancer, and hence it has recently received increased attention of cancer researchers. After myriad investigations on HSF-1, the field has advanced to the phase where there is consensus that finding a potent and selective pharmacological inhibitor for this transcription factor will be a major break-through in the treatment of various human cancers. Presently, all reported inhibitors have their limitations, made evident at different stages of clinical trials. This brief account summarizes the advances with tested natural products as HSF-1 inhibitors and highlights the necessity of phytochemistry in this endeavor of discovering a potent pharmacological HSF-1 inhibitor.
, , Nam Van Le, Thi Thu Phuong Tran, Jong Seong Lee, Sae Kwang Ku, Han-Gon Choi, ,
International Journal of Pharmaceutics, Volume 528, pp 692-704; doi:10.1016/j.ijpharm.2017.06.069

Xuerong Zhao, Jianping Wang, , Qian Xu, Enhong Zhao, Xin Zheng, Huachuan Zheng, Shuang Zhao, Shi Ding
Published: 21 June 2017
Oncology Letters, Volume 14, pp 2177-2185; doi:10.3892/ol.2017.6442

Abstract:
The present study investigated the effects of HSP90 inhibitor 17-allylamino-17-demethoxygeldanamycin (17-AAG) on apoptosis and the cell cycle of the HCT-116 human colon carcinoma cell line, with the aim of elucidating their underlying mechanisms. MTT was used to examine the inhibitory effects of 17-AAG on the proliferation of HCT-116 cells at various time points and doses. The cells were stained with Annexin V-fluorescein isothiocyanate/propidium iodide and evaluated by flow cytometry. The expression of signal transducer and activator of transcription (STAT)3, cyclin D1, cytochrome c (cyt-c), caspase 9 and caspase 3 at the mRNA and protein level was determined using reverse transcription-polymerase chain reaction and western blotting. Treatment with 17-AAG at a concentration of 1.25–20 mg/l for 24 and 48 h significantly inhibited the proliferation of HCT-116 cells in a time-dependent and concentration-dependent manner. Treatment with 17-AAG at concentrations of 1.25, 2.5 and 5 mg/l for 48 h significantly induced apoptosis and cell cycle arrest in HCT-116 cells. Exposure to 17-AAG at concentrations of 1.25, 2.5 and 5 mg/l for 48 h significantly downregulated the mRNA and protein expression of STAT3 and cyclin D1, but upregulated cyt-c, caspase 9 and caspase 3 in a concentration-dependent manner in HCT-116 cells. Therefore 17-AAG is able to inhibit cell proliferation, inducing apoptosis and G1 stage cell cycle arrest by downregulating the expression of cyclin D1, and promoting the mitochondria apoptosis by downregulating STAT3 in HCT-116 cells.
Qiyu Feng, Chengliang Zhang, David Lum, Joseph E. Druso, Bryant Blank, Kristin F. Wilson, Alana Welm, Marc A. Antonyak, Richard A. Cerione
Nature Communications, Volume 8; doi:10.1038/ncomms14450

Abstract:
Non-classical secretory vesicles, collectively referred to as extracellular vesicles (EVs), have been implicated in different aspects of cancer cell survival and metastasis. Here, we describe how a specific class of EVs, called microvesicles (MVs), activates VEGF receptors and tumour angiogenesis through a unique 90 kDa form of VEGF (VEGF90K). We show that VEGF90K is generated by the crosslinking of VEGF165, catalysed by the enzyme tissue transglutaminase, and associates with MVs through its interaction with the chaperone Hsp90. We further demonstrate that MV-associated VEGF90K has a weakened affinity for Bevacizumab, causing Bevacizumab to be ineffective in blocking MV-dependent VEGF receptor activation. However, treatment with an Hsp90 inhibitor releases VEGF90K from MVs, restoring the sensitivity of VEGF90K to Bevacizumab. These findings reveal a novel mechanism by which cancer cell-derived MVs influence the tumour microenvironment and highlight the importance of recognizing their unique properties when considering drug treatment strategies.
Longze Sha, Xueqin Wang, Jing Li, Xinze Shi, Liwen Wu, Yan Shen,
Journal of Experimental Medicine, Volume 214, pp 547-563; doi:10.1084/jem.20160667

Abstract:
The glutamate transporter GLT-1 is critical for the maintenance of low interstitial glutamate concentrations. Loss of GLT-1 is commonly observed in neurological disorders, including temporal lobe epilepsy (TLE). Despite the hypothesis that targeting the mechanisms of GLT-1 deficiency may be a novel strategy for treating drug-resistant epilepsy, the underlying molecular cascade remains largely unknown. Here, we show that Hsp90β is up-regulated in reactive astrocytes of the epileptic hippocampus in patients with TLE and mouse models of epilepsy. Inhibition of Hsp90, but not Hsp70, increased GLT-1 levels. Mechanistically, Hsp90β recruits GLT-1 to the 20S proteasome, thereby promoting GLT-1 degradation. Hsp90 inhibitor prevents GLT-1 degradation by disrupting the association between Hsp90β and GLT-1. Using a model of TLE, we demonstrated that long-term systemic administration of 17AAG dramatically suppressed spontaneous recurrent seizures and ameliorated astrogliosis. Overall, these results suggest that up-regulation of GLT-1 by inhibiting Hsp90β in reactive astrocytes may be a potential therapeutic target for the treatment of epilepsy and excitotoxicity.
Published: 20 June 2016
Molecules, Volume 21; doi:10.3390/molecules21060771

Abstract:
A series of pyrazolo[3,4-d]pyrimidine derivatives related to allopurinol has been synthesized and evaluated for its cytotoxicity against a panel of three cancer cell lines as well as its xanthine oxidase (XOD) inhibitory activities. Among them, compound 4 showed potent cytotoxicity with IC50 values of 25.5 and 35.2 μM against human hepatoma carcinoma cell lines, BEL-7402 and SMMC-7221, respectively. The anticancer activity of 4 was comparable to that of Tanespimycin (17-N-allylamino-17-demethoxy geldanamycin, 17-AAG) that inhibited the growth of BEL-7402 and SMMC-7221 cells at IC50 values of 12.4 and 9.85 μM, respectively. However, unlike allopurinol, which is also a strong inhibitor of XOD, compound 4 is a much weaker XOD inhibitor, suggesting that the anticancer activities of the allopurinol derivatives may not be associated with XOD inhibition. Moreover, the cytotoxicity of 4 toward normal cells is significantly lower than that of 17-AAG, making 4 a promising lead compound for further optimization of structure-activity relationships that may lead to anticancer agents of clinical utility.
Xuerong Zhao, Jianping Wang, Lijun Xiao, Qian Xu, Enhong Zhao, Xin Zheng, Huachuan Zheng, Shuang Zhao, Shi Ding
Molecular Medicine Reports, Volume 14, pp 1067-74; doi:10.3892/mmr.2016.5365

Abstract:
As a heat shock protein 90 inhibitor, 17-allylamino-17‑demethoxygeldanamycin (17-AAG) has been studied in numerous types of cancer, however the effects of 17-AAG on apoptosis and the cell cycle of H446 cells remain unclear. In the current study, the MTT method was used to evaluate the inhibitory effects of different durations and doses of 17‑AAG treatment on the proliferation of H446 cells. The cells were stained with Annexin-fluorescein isothiocyanate/propidium iodide and measured by flow cytometry, and the gene and protein expression levels of signal transducer and activator of transcription 3 (STAT3), survivin, cyclin D1, cyt‑C, caspase 9 and caspase 3 were determined by reverse transcription‑quantitative polymerase chain reaction and western blot analysis. The results indicated that with treatment with 1.25‑20 mg/l 17‑AAG for 24 and 48 h, significant inhibition of H446 cell proliferation was observed in a time‑ and dose‑dependent manner. With treatment of 3.125, 6.25 and 12.5 mg/l 17‑AAG for 48 h, significant apoptosis and cell cycle arrest was observed. The results indicated that the gene and protein expression levels of STAT3, survivin and cyclin D1 were downregulated, and cyt‑C, caspase 9 and caspase 3 were upregulated by 17‑AAG in a dose-dependent manner when the cells were treated with 3.125 and 6.25 mg/l 17-AAG for 48 h. The results indicated that 17‑AAG is able to inhibit the cell proliferation, induce apoptosis and G2/M arrest and downregulate the gene and protein expression levels of STAT3, survivin and cyclin D1, and upregulate gene and protein expression of cyt‑C, caspase 9, caspase 3.
, Susan L. Morris-Natschke,
Published: 11 September 2015
by Wiley
Medicinal Research Reviews, Volume 36, pp 32-91; doi:10.1002/med.21377

The publisher has not yet granted permission to display this abstract.
NeuroMolecular Medicine, Volume 17, pp 147-157; doi:10.1007/s12017-015-8346-x

The publisher has not yet granted permission to display this abstract.
, Herui Wang, Dongwang Zhu, Christopher S. Hong, , Chao Zhang, Yan Li, Barbara Ikejiri, ,
Proceedings of the National Academy of Sciences, Volume 112, pp 1137-1142; doi:10.1073/pnas.1424288112

Abstract:
Gaucher disease is caused by mutations of the GBA1 gene, which encodes the lysosomal anchored gluococerebrosidase (GCase). GBA1 mutations commonly result in protein misfolding, abnormal chaperone recognition, and premature degradation, but are less likely to affect catalytic activity. In the present study, we demonstrate that the Hsp90/HOP/Cdc37 complex recruits Hsp27 after recognition of GCase mutants with subsequent targeting of GCase mutant peptides to degradation mechanisms such as VCP and the 26S proteasome. Inhibition of Hsp27 not only increased the quantity of enzyme but also enhanced GCase activity in fibroblasts derived from patients with Gaucher disease. These findings provide insight into a possible therapeutic strategy for protein misfolding diseases by correcting chaperone binding and altering subsequent downstream patterns of protein degradation.
Carmen Avendaño,
Medicinal Chemistry of Anticancer Drugs pp 493-560; doi:10.1016/b978-0-444-62649-3.00011-9

The publisher has not yet granted permission to display this abstract.
Gagan S. Thangjam, Chistiana Dimitropoulou, , Nektarios Barabutis, Mary C. Shaw, , Chistopher M. Wallace, David J. Fulton, Vijay Patel, John D. Catravas
American Journal of Respiratory Cell and Molecular Biology, Volume 50, pp 942-952; doi:10.1165/rcmb.2013-0214oc

The publisher has not yet granted permission to display this abstract.
Weiwei Guo, Lichong Yan, Ling Yang, Xiaoyu Liu, Qiukai E, Peiye Gao, Xiaofei Ye, ,
Published: 17 January 2014
PLOS ONE, Volume 9; doi:10.1371/journal.pone.0085766

Abstract:
Heat shock protein 90 (HSP90) inhibitors are potential drugs for cancer therapy. The inhibition of HSP90 on cancer cell growth largely through degrading client proteins, like Akt and p53, therefore, triggering cancer cell apoptosis. Here, we show that the HSP90 inhibitor 17-AAG can induce the expression of GRP75, a member of heat shock protein 70 (HSP70) family, which, in turn, attenuates the anti-growth effect of HSP90 inhibition on cancer cells. Additionally, 17-AAG enhanced binding of GRP75 and p53, resulting in the retention of p53 in the cytoplasm. Blocking GRP75 with its inhibitor MKT-077 potentiated the anti-tumor effects of 17-AAG by disrupting the formation of GRP75-p53 complexes, thereby facilitating translocation of p53 into the nuclei and leading to the induction of apoptosis-related genes. Finally, dual inhibition of HSP90 and GRP75 was found to significantly inhibit tumor growth in a liver cancer xenograft model. In conclusion, the GRP75 inhibitor MKT-077 enhances 17-AAG-induced apoptosis in HCCs and increases p53-mediated inhibition of tumor growth in vivo. Dual targeting of GRP75 and HSP90 may be a useful strategy for the treatment of HCCs.
, Kazusaku Kamiya, Katsuhisa Ikeda, Naofumi Yui, Motoko Chiga, Eisei Sohara, Tatemitu Rai, Sei Sakaki, Shinich Uchida
Biochemical and Biophysical Research Communications, Volume 441, pp 544-549; doi:10.1016/j.bbrc.2013.10.129

Page of 1
Articles per Page
by
Show export options
  Select all
Back to Top Top