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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.

ABSTRACT: Pancreatic ductal adenocarcinoma (PDAC) is an aggressive, incurable cancer with a 20% 1 year survival rate. While standard-of-care therapy can prolong life in a small fraction of cases, PDAC is inherently resistant to current treatments, and novel therapies are urgently required. Histone deacetylase (HDAC) inhibitors are effective in killing pancreatic cancer cells in in vitro PDAC studies, and although there are a few clinical studies investigating combination therapy including HDAC inhibitors, no HDAC drug or combination therapy with an HDAC drug has been approved for the treatment of PDAC. We developed an inhibitor of HDACs, AES-135, that exhibits nanomolar inhibitory activity against HDAC3, HDAC6, and HDAC11 in biochemical assays. In a three-dimensional coculture model, AES-135 kills low-passage patient-derived tumor spheroids selectively over surrounding cancer-associated fibroblasts and has excellent pharmacokinetic properties in vivo. In an orthotopic murine model of pancreatic cancer, AES-135 prolongs survival significantly, therefore representing a candidate for further preclinical testing.

SUBMITTER: Shouksmith AE

PROVIDER: S-EPMC7190078 | biostudies-literature | 2019 Mar

REPOSITORIES: biostudies-literature

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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.

Shouksmith Andrew E AE Shah Fenil F Grimard Michelle L ML Gawel Justyna M JM Raouf Yasir S YS Geletu Mulu M Berger-Becvar Angelika A de Araujo Elvin D ED Luchman H Artee HA Heaton William L WL Bakhshinyan David D Adile Ashley A AA Venugopal Chitra C O'Hare Thomas T Deininger Michael W MW Singh Sheila K SK Konieczny Stephen F SF Weiss Samuel S Fishel Melissa L ML Gunning Patrick T PT

Journal of medicinal chemistry 20190306 5

Pancreatic ductal adenocarcinoma (PDAC) is an aggressive, incurable cancer with a 20% 1 year survival rate. While standard-of-care therapy can prolong life in a small fraction of cases, PDAC is inherently resistant to current treatments, and novel therapies are urgently required. Histone deacetylase (HDAC) inhibitors are effective in killing pancreatic cancer cells in in vitro PDAC studies, and although there are a few clinical studies investigating combination therapy including HDAC inhibitors, ...[more]

PMID: 30776234

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Project description:BACKGROUND: Cysteamine, an anti-oxidant aminothiol, is the treatment of choice for nephropathic cystinosis, a rare lysosomal storage disease. Cysteamine is a chemo-sensitization and radioprotection agent and its antitumor effects have been investigated in various tumor cell lines and chemical induced carcinogenesis. Here, we investigated whether cysteamine has anti-tumor and anti-metastatic effects in transplantable human pancreatic cancer, an aggressive metastatic disease. METHODOLOGY/PRINCIPAL FINDINGS: Cysteamine's anti-invasion effects were studied by matrigel invasion and cell migration assays in 10 pancreatic cancer cell lines. To study mechanism of action, we examined cell viability and matrix metalloproteinases (MMPs) activity in the cysteamine-treated cells. We also examined cysteamine's anti-metastasis effect in two orthotopic murine models of human pancreatic cancer by measuring peritoneal metastasis and survival of animals. Cysteamine inhibited both migration and invasion of all ten pancreatic cancer cell lines at concentrations (<25 mM) that caused no toxicity to cells. It significantly decreased MMPs activity (IC(50) 38-460 µM) and zymographic gelatinase activity in a dose dependent manner in vitro and in vivo; while mRNA and protein levels of MMP-9, MMP-12 and MMP-14 were slightly increased using the highest cysteamine concentration. In vivo, cysteamine significantly decreased metastasis in two established pancreatic tumor models, although it did not affect the size of primary tumors. Additionally, cysteamine prolonged survival of mice in a dose-dependent manner without causing any toxicity. Similar to the in vitro results, MMP activity was significantly decreased in animal tumors treated with cysteamine. Cysteamine had no clinical or preclinical adverse effects in the host even at the highest dose. CONCLUSIONS/SIGNIFICANCE: Our results suggest that cysteamine, an agent with a proven safety profile, may be useful for inhibition of metastasis and prolonging the survival of a host with pancreatic cancer.

Dataset Information

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

Publications

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

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