Identification and Characterization of AES-135, a Hydroxamic Acid-Based HDAC Inhibitor That Prolongs Survival in an Orthotopic Mouse Model of Pancreatic Cancer

Shouksmith, Andrew E.; Shah, Fenil; Grimard, Michelle; Gawel, Justyna M.; Raouf, Yasir S.; Geletu, Mulu; Berger-Becvar, Angelika; Araujo, Elvin D. de; Luchman, H. Artee; Heaton, William L.; Bakhshinyan, David; Adile, Ashley; Venugopal, Chitra; O’Hare, Thomas; Deininger, Michael W.; Singh, Sheila K.; Konieczny, Stephen F.; Weiss, Samuel; Fishel, Melissa L.; Gunning, Patrick T.

doi:10.1021/acs.jmedchem.8b01957

Cited by 32 publications

(25 citation statements)

References 47 publications

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“…21,22 HDACs are overexpressed in different tumors types, and HDAC expression levels are closely related to prognosis. [23][24][25] Inhibition of HDACs can induce cell growth arrest and apoptosis in a variety of malignant cells, including breast cancer cells, 26 prostate cancer cells, 27 HCC cells, 28 pancreatic cancer cells, 29 lymphoma cells, 30 and lung cancer cells. 31 Thus, HDACs are considered therapeutic targets for various tumors.…”

Section: Introductionmentioning

confidence: 99%

LukS-PV Inhibits Hepatocellular Carcinoma Progression by Downregulating HDAC2 Expression

Wang

Qiang

et al. 2020

Molecular Therapy - Oncolytics

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Hepatocellular carcinoma (HCC) is a common malignant tumor. LukS-PV is the S component of Panton-Valetine leukocidin (PVL), which is secreted by Staphylococcus aureus. This study investigated the effects of LukS-PV on the proliferation, apoptosis, and cell-cycle progression of HCC cells and the mechanisms of its activity. The HCC cells were treated with different LukS-PV concentrations in vitro. Cell Counting Kit-8 and 5-Ethynyl-2'-deoxyuridine (EdU) assays were used to study cell proliferation. Flow cytometry was used to measure apoptosis and cell-cycle progression. Quantitative reverse transcriptase PCR and western blot assays were used to determine mRNA and protein expression levels. Xenograft experiments were performed to determine the in vivo antitumor effect of LukS-PV. Immunostaining was performed to analyze Ki-67 and HDAC2 (histone deacetylase 2) expression. Our results showed that LukS-PV inhibited cell proliferation and induced apoptosis in a concentration-dependent manner in HCC cell lines. LukS-PV also can induce cell-cycle arrest. Moreover, we discovered that LukS-PV attenuated HDAC2 expression and upregulated PTEN; phosphorylated AKT was also reduced. Further studies demonstrated that LukS-PV treatment significantly reduced tumor growth in nude mice and suppressed Ki-67 and HDAC2 levels. Our data revealed a vital role of LukS-PV in suppressing HCC progression by downregulating HDAC2 and upregulating PTEN.

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Section: Introductionmentioning

confidence: 99%

LukS-PV Inhibits Hepatocellular Carcinoma Progression by Downregulating HDAC2 Expression

Wang

Qiang

et al. 2020

Molecular Therapy - Oncolytics

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“…A previously described high-throughput in vitro glutathione-reactivity assay was conducted, where compounds were incubated in the presence of glutathione (GSH) and the formation of a GSH-compound adduct was monitored over time via LC/MS/MS. 50 Fluorinated analogues 3 and 4 were found to react readily with glutathione, which precluded further advancement ( Table S1a ). The exceptional picomolar HDAC6 potency of 5 and moderate GSH stability (half-life of 20 min) warranted further ADME analysis.…”

Section: Resultsmentioning

confidence: 99%

Development of HDAC Inhibitors Exhibiting Therapeutic Potential in T-Cell Prolymphocytic Leukemia

et al. 2021

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Epigenetic targeting has emerged as an efficacious therapy for hematological cancers. The rare and incurable T-cell prolymphocytic leukemia (T-PLL) is known for its aggressive clinical course. Current epigenetic agents such as histone deacetylase (HDAC) inhibitors are increasingly used for targeted therapy. Through a structure–activity relationship (SAR) study, we developed an HDAC6 inhibitor KT-531, which exhibited higher potency in T-PLL compared to other hematological cancers. KT-531 displayed strong HDAC6 inhibitory potency and selectivity, on-target biological activity, and a safe therapeutic window in nontransformed cell lines. In primary T-PLL patient cells, where HDAC6 was found to be overexpressed, KT-531 exhibited strong biological responses, and safety in healthy donor samples. Notably, combination studies in T-PLL patient samples demonstrated KT-531 synergizes with approved cancer drugs, bendamustine, idasanutlin, and venetoclax. Our work suggests HDAC inhibition in T-PLL could afford sufficient therapeutic windows to achieve durable remission either as stand-alone or in combination with targeted drugs.

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“…HDAC3 is linked to the development of smoking-induced PDAC through regulation of the cytokine IL-6 and interactions between cancer cells and tumor promoting macrophages [18]. The new HDACi AES-135 targets HDAC3, HDAC6, HDAC11, and is effective against PDAC cells in vitro and in mice [19]. Other HDACs, including HDAC1, HDAC7, and HDAC8 are likewise necessary for the survival of such tumor cells [17].…”

Section: Introductionmentioning

confidence: 99%

Class 1 Histone Deacetylases and Ataxia-Telangiectasia Mutated Kinase Control the Survival of Murine Pancreatic Cancer Cells upon dNTP Depletion

Nguyen

Dzulko

Murr

et al. 2021

Cells

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Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive disease with a dismal prognosis. Here, we show how an inhibition of de novo dNTP synthesis by the ribonucleotide reductase (RNR) inhibitor hydroxyurea and an inhibition of epigenetic modifiers of the histone deacetylase (HDAC) family affect short-term cultured primary murine PDAC cells. We used clinically relevant doses of hydroxyurea and the class 1 HDAC inhibitor entinostat. We analyzed the cells by flow cytometry and immunoblot. Regarding the induction of apoptosis and DNA replication stress, hydroxyurea and the novel RNR inhibitor COH29 are superior to the topoisomerase-1 inhibitor irinotecan which is used to treat PDAC. Entinostat promotes the induction of DNA replication stress by hydroxyurea. This is associated with an increase in the PP2A subunit PR130/PPP2R3A and a reduction of the ribonucleotide reductase subunit RRM2 and the DNA repair protein RAD51. We further show that class 1 HDAC activity promotes the hydroxyurea-induced activation of the checkpoint kinase ataxia-telangiectasia mutated (ATM). Unlike in other cell systems, ATM is pro-apoptotic in hydroxyurea-treated murine PDAC cells. These data reveal novel insights into a cytotoxic, ATM-regulated, and HDAC-dependent replication stress program in PDAC cells.

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Identification and Characterization of AES-135, a Hydroxamic Acid-Based HDAC Inhibitor That Prolongs Survival in an Orthotopic Mouse Model of Pancreatic Cancer

Cited by 32 publications

References 47 publications

LukS-PV Inhibits Hepatocellular Carcinoma Progression by Downregulating HDAC2 Expression

LukS-PV Inhibits Hepatocellular Carcinoma Progression by Downregulating HDAC2 Expression

Development of HDAC Inhibitors Exhibiting Therapeutic Potential in T-Cell Prolymphocytic Leukemia

Class 1 Histone Deacetylases and Ataxia-Telangiectasia Mutated Kinase Control the Survival of Murine Pancreatic Cancer Cells upon dNTP Depletion

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