A novel HDAC6 inhibitor Tubastatin A: Controls HDAC6-p97/VCP-mediated ubiquitination-autophagy turnover and reverses Temozolomide-induced ER stress-tolerance in GBM cells

Li, Zongyang; Zhang, Ce; Zhang, Yuan; Chen, Lei; Chen, Baodong; Zhang, Xiejun; Li, Weiping

doi:10.1016/j.canlet.2017.01.025

Cited by 46 publications

(29 citation statements)

References 35 publications

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“…Furthermore, it has been demonstrated that VCP participates in many cellular activities via its adaptor proteins (Buchberger et al ., ; Zhang et al ., ; Bulfer et al ., ; Hanzelmann & Schindelin, ). Our previous study and other studies showed that VCP is not only directly involved in the activation of transcriptional factors, such as NF‐κb and Stat3 (Lizano et al ., ) in cardiomyocytes, but also involved in the regulation of the proteasome and ubiquitin system in some cell types (Vekaria et al ., ; Li et al ., ). These data together indicate that VCP may be able to regulate the synthesis and degradation of other proteins including its cofactors or adaptor proteins.…”

Section: Discussionmentioning

confidence: 97%

The valosin‐containing protein is a novel repressor of cardiomyocyte hypertrophy induced by pressure overload

Zhou

Stoll

et al. 2017

Aging Cell

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SummaryHypertension‐induced left ventricular hypertrophy (LVH) is an independent risk factor for heart failure. Regression of LVH has emerged as a major goal in the treatment of hypertensive patients. Here, we tested our hypothesis that the valosin‐containing protein (VCP), an ATPase associate protein, is a novel repressor of cardiomyocyte hypertrophy under the pressure overload stress. Left ventricular hypertrophy (LVH) was determined by echocardiography in 4‐month male spontaneously hypertensive rats (SHRs) vs. age‐matched normotensive Wistar Kyoto (WKY) rats. VCP expression was found to be significantly downregulated in the left ventricle (LV) tissues from SHRs vs. WKY rats. Pressure overload was induced by transverse aortic constriction (TAC) in wild‐type (WT) mice. At the end of 2 weeks, mice with TAC developed significant LVH whereas the cardiac function remained unchanged. A significant reduction of VCP at both the mRNA and protein levels in hypertrophic LV tissue was found in TAC WT mice compared to sham controls. Valosin‐containing protein VCP expression was also observed to be time‐ and dose‐dependently reduced in vitro in isolated neonatal rat cardiomyocytes upon the treatment of angiotensin II. Conversely, transgenic (TG) mice with cardiac‐specific overexpression of VCP showed a significant repression in TAC‐induced LVH vs. litter‐matched WT controls upon 2‐week TAC. TAC‐induced activation of the mechanistic target of rapamycin complex 1 (mTORC1) signaling observed in WT mice LVs was also significantly blunted in VCP TG mice. In conclusion, VCP acts as a novel repressor that is able to prevent cardiomyocyte hypertrophy from pressure overload by modulating the mTORC1 signaling pathway.

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Section: Discussionmentioning

confidence: 97%

The valosin‐containing protein is a novel repressor of cardiomyocyte hypertrophy induced by pressure overload

Zhou

Stoll

et al. 2017

Aging Cell

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“…Resistance to the chemotherapy cisplatin has been shown to be due to autophagy induction in ovarian and esophageal cancer 123,124 , and via hypoxia induced autophagy in lung cancer 125 . Like in melanoma 115 , autophagy induction due to an ER stress response results in resistance in primary patient chronic lymphocytic leukemia cells to cyclin dependent kinase (CDK) inhibitors 126 and in resistance in glioblastoma cell lines to HDAC inhibitors such as Tubastatin A 127 . As the link between autophagy and resistance to chemotherapy is strengthened, autophagy will undoubtedly continue to develop as a promising target in cancer therapy 128–132 .…”

Section: Targeting Autophagy: a Good Idea?mentioning

confidence: 99%

Targeting autophagy in cancer

2017

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Preface Autophagy is a mechanism by which cellular material is delivered to lysosomes for degradation allowing basal turnover of cell components and providing energy and macromolecular precursors. Autophagy has opposing, context-dependent roles in cancer and interventions to both stimulate and inhibit autophagy have been proposed as cancer therapies. This has caused therapeutic targeting of autophagy in cancer to be sometimes viewed as controversial. Here we suggest a way forward for effective targeting of autophagy by understanding the context-dependent roles of autophagy and capitalizing on modern approaches to clinical trial design.

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“…These resultsh ighlightedh ow modifications of the ZBGc ould represent av aluables trategy to modulate class selectivity in these ligands and provided information about how to address HDAC6 selectivity.T his topic is of current interest, as HDAC6 has recently been shown to be an ew possible target for the treatment of glioblastoma and multiple myeloma. [18,19] Interestingly,p otent and selective HDAC6 inhibitors with an a-thioacetimide ZBG have been recently reported for possible use in the treatment of central nervoussystem disorders. [20] Few largazole analogues with ZBGs incorporating an aromatic moiety and as econd heteroatom for metal chelation were reported by Tillekeratne and collaborators.…”

Section: Analogues With Modified Warheadmentioning

confidence: 99%

Largazole Analogues as Histone Deacetylase Inhibitors and Anticancer Agents: An Overview of Structure–Activity Relationships

Poli

Fabio

Ferrante³

et al. 2017

ChemMedChem

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Since the time of its identification, the natural compound largazole rapidly caught the attention of the medicinal chemistry community for its impressive potency as an inhibitor of histone deacetylases (HDACs) and its strong antiproliferative activity against a broad panel of cancer cell lines. The design of largazole analogues is an expanding field of study, due to their remarkable potential as novel anticancer therapeutics. At present, a large ensemble of largazole analogues has been reported, allowing the identification of important structure-activity relationships (SAR) that can guide the design of novel compounds with improved HDAC inhibitory profiles, anticancer activity, and pharmacokinetic properties. The aim of this review is to concisely summarize the information obtained by biological evaluations of the various largazole analogues reported to date, with particular attention given to the latest analogues, as well as to analyze the various SAR obtained from this data, with the purpose of providing useful guidelines for the development of novel potent and selective HDAC inhibitors to be used as anticancer agents.

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A novel HDAC6 inhibitor Tubastatin A: Controls HDAC6-p97/VCP-mediated ubiquitination-autophagy turnover and reverses Temozolomide-induced ER stress-tolerance in GBM cells

Cited by 46 publications

References 35 publications

The valosin‐containing protein is a novel repressor of cardiomyocyte hypertrophy induced by pressure overload

The valosin‐containing protein is a novel repressor of cardiomyocyte hypertrophy induced by pressure overload

Targeting autophagy in cancer

Largazole Analogues as Histone Deacetylase Inhibitors and Anticancer Agents: An Overview of Structure–Activity Relationships

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