Tesaglitazar, a Dual PPAR-α/γ Agonist, Hamster Carcinogenicity, Investigative Animal and Clinical Studies

Lindblom, Per Henrik; Berg, Anna‐Lena; Zhang, Hui; Westerberg, R.B.; Tugwood, Jonathan; Lundgren, Hanna; Marcusson-Ståhl, Maritha; Sjögren, Niclas; Blomgren, Bo; Skånberg, Inger; Evans, J.G.; Hellmold, Heike

doi:10.1177/0192623311429972

Cited by 10 publications

(7 citation statements)

References 40 publications

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“…Following plating, cells were treated on Days 4 and 8 with media containing 5% serum, 3% RGF Matrigel, and inhibitors as indicated. On Day 12, spheroids were analyzed using Thermo ArrayScan high-content imaging system (43). Images of 3D structures were captured by ArrayScan using a 2.5× objective for TdTomato and EGFP; then 2D projections were processed to quantify differences in total intensity and total area of both CAFs and tumor.…”

Section: Methodsmentioning

confidence: 99%

Regulation of HIF1α under Hypoxia by APE1/Ref-1 Impacts CA9 Expression: Dual Targeting in Patient-Derived 3D Pancreatic Cancer Models

Logsdon

Grimard

Luo

et al. 2016

Molecular Cancer Therapeutics

133

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Pancreatic ductal adenocarcinoma (PDAC) is the 4th leading cause of cancer-related mortality in the United States. Aggressive treatment regimens have not changed the disease course, and the median survival has just recently reached a year. Several mechanisms are proposed to play a role in PDAC therapeutic resistance, including hypoxia, which creates a more aggressive phenotype with increased metastatic potential and impaired therapeutic efficacy. AP Endonuclease-1/Redox Effector Factor 1 (APE1/Ref-1) is a multi-functional protein possessing a DNA repair function in base excision repair and the ability to reduce oxidized transcription factors, enabling them to bind to their DNA target sequences. APE1/Ref-1 regulates several transcription factors involved in survival mechanisms, tumor growth, and hypoxia signaling. Here, we explore the mechanisms underlying PDAC cell responses to hypoxia and modulation of APE1/Ref-1 redox signaling activity, which regulates the transcriptional activation of hypoxia inducible factor 1 alpha (HIF1α). Carbonic anhydrase IX (CA9) is regulated by HIF1α and functions as part of the cellular response to hypoxia to regulate intracellular pH, thereby promoting cell survival. We hypothesized that modulating APE1/Ref-1 function will block activation of downstream transcription factors, STAT3 and HIF1α, interfering with hypoxia-induced gene expression. We demonstrate APE1/Ref-1 inhibition in patient-derived and established PDAC cells results in decreased HIF1α–mediated induction of CA9. Furthermore, an ex vivo 3D tumor co-culture model demonstrates dramatic enhancement of APE1/Ref-1-induced cell killing upon dual-targeting of APE1/Ref-1 and CA9. Both APE1/Ref-1 and CA9 are under clinical development, therefore these studies have the potential to direct novel PDAC therapeutic treatment.

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Section: Methodsmentioning

confidence: 99%

Regulation of HIF1α under Hypoxia by APE1/Ref-1 Impacts CA9 Expression: Dual Targeting in Patient-Derived 3D Pancreatic Cancer Models

Logsdon

Grimard

Luo

et al. 2016

Molecular Cancer Therapeutics

133

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“…The vehicle control was DMSO, was less than 0.01% of the volume, and was equivalent in each well. On Day 12, either Alamar blue reagent (LifeTechnologies) was added to each well (10μL/well) and incubated for 4 hr or spheroids were analyzed using Thermo ArrayScan high-content imaging system (55, 56). For Alamar blue assays, fluorescence reading at 544, 590 nM was then taken and used to assess survival following STAT3 inhibition.…”

Section: Methodsmentioning

confidence: 99%

Applying Small Molecule Signal Transducer and Activator of Transcription-3 (STAT3) Protein Inhibitors as Pancreatic Cancer Therapeutics

Arpin

Mac

Jiang

et al. 2016

Molecular Cancer Therapeutics

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Constitutively activated Signal Transducer and Activator of Transcription 3 (STAT3) protein has been found to be a key regulator of pancreatic cancer and a target for molecular therapeutic intervention. In this study PG-S3-001, a small molecule derived from the SH-4-54 class of STAT3 inhibitors, was found to inhibit patient-derived pancreatic cancer cell proliferation in vitro and in vivo in the low μM range. PG-S3-001 binds the STAT3 protein potently, Kd = 324 nM by SPR, showed no effect in a kinome screen (> 100 cancer-relevant kinases). In vitro studies demonstrated potent cell killing as well as inhibition of STAT3 activation in pancreatic cancer cells. To better model the tumor and its microenvironment, we utilized 3-Dimensional (3D) cultures of patient-derived pancreatic cancer cells in the absence and presence of cancer-associated fibroblasts (CAFs). In this co-culture model, inhibition of tumor growth is maintained following STAT3 inhibition in the presence of CAFs. Confocal microscopy was used to verify tumor cell death following treatment of 3D co-cultures with PG-S3-001. The 3D model was predictive of in vivo efficacy as significant tumor growth inhibition was observed upon administration of PG-S3-001. These studies showed that the inhibition of STAT3 was able to impact the survival of tumor cells in a relevant 3D model, as well as in a xenograft model using patient-derived cells.

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“… 64 , 180 3D cultures were treated on Days 4 and 8 after plating with inhibitors as indicated and analyzed using Thermo ArrayScan high-content imaging system on Day 12 after plating. 276 …”

Section: The Futurementioning

confidence: 99%

Exploiting the Ref-1-APE1 node in cancer signaling and other diseases: from bench to clinic

et al. 2017

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Reduction-oxidation factor 1-apurinic/apyrimidinic endonuclease (Ref-1/APE1) is a critical node in tumor cells, both as a redox regulator of transcription factor activation and as part of the DNA damage response. As a redox signaling protein, Ref-1/APE1 enhances the transcriptional activity of STAT3, HIF-1α, nuclear factor kappa B, and other transcription factors to promote growth, migration, and survival in tumor cells as well as inflammation and angiogenesis in the tumor microenvironment. Ref-1/APE1 is activated in a variety of cancers, including prostate, colon, pancreatic, ovarian, lung and leukemias, leading to increased aggressiveness. Transcription factors downstream of Ref-1/APE1 are key contributors to many cancers, and Ref-1/APE1 redox signaling inhibition slows growth and progression in a number of tumor types. Ref-1/APE1 inhibition is also highly effective when paired with other drugs, including standard-of-care therapies and therapies targeting pathways affected by Ref-1/APE1 redox signaling. Additionally, Ref-1/APE1 plays a role in a variety of other indications, such as retinopathy, inflammation, and neuropathy. In this review, we discuss the functional consequences of activation of the Ref-1/APE1 node in cancer and other diseases, as well as potential therapies targeting Ref-1/APE1 and related pathways in relevant diseases. APX3330, a novel oral anticancer agent and the first drug to target Ref-1/APE1 for cancer is entering clinical trials and will be explored in various cancers and other diseases bringing bench discoveries to the clinic.

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Tesaglitazar, a Dual PPAR-α/γ Agonist, Hamster Carcinogenicity, Investigative Animal and Clinical Studies

Cited by 10 publications

References 40 publications

Regulation of HIF1α under Hypoxia by APE1/Ref-1 Impacts CA9 Expression: Dual Targeting in Patient-Derived 3D Pancreatic Cancer Models

Regulation of HIF1α under Hypoxia by APE1/Ref-1 Impacts CA9 Expression: Dual Targeting in Patient-Derived 3D Pancreatic Cancer Models

Applying Small Molecule Signal Transducer and Activator of Transcription-3 (STAT3) Protein Inhibitors as Pancreatic Cancer Therapeutics

Exploiting the Ref-1-APE1 node in cancer signaling and other diseases: from bench to clinic

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