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Translating the Anti-Tumor/Anti-Cachectic Activity of AR-42, a Novel HDAC Inhibitor, into Pancreatic Cancer Therapy

Henderson, Sally E
http://orcid.org/0000-0002-2166-0898
http://rave.ohiolink.edu/etdc/view?acc_num=osu1495801301660324

Abstract Details

2017, Doctor of Philosophy, Ohio State University, Comparative and Veterinary Medicine.
Pancreatic cancer is the 3rd leading cause of cancer death in the United States and has a 5-year survival of less than 9% for all stages. Furthermore, cachexia, defined as severe weight loss due to depletion of muscle mass that is not reversible with conventional nutritional support, is seen in 85% of pancreatic cancer patients and contributes significantly to morbidity and mortality. Therefore, there is an urgent need to develop novel therapeutics that target tumor growth and muscle wasting in order to improve clinical outcomes. The first part of this study was aimed at evaluating the efficacy of AR-42, a novel histone deacetylase (HDAC) inhibitor developed in our laboratory, in suppressing tumor growth in mouse models of pancreatic cancer. The in vitro anti-proliferative activity of AR-42 was evaluated in six human pancreatic cancer cell lines. An AsPC-1 subcutaneous xenograft and transgenic KPfl/flC (LSL-KrasG12D;Trp53flox/flox;Pdx-1-Cre) mouse models of pancreatic cancer were used to evaluate the in vivo efficacy of AR-42 in suppressing tumor growth and/or muscle wasting. Growth suppression in AR-42-treated cells was observed in all six human pancreatic cancer cell lines with dose-dependent modulation of proliferation and apoptotic markers and hallmark features of HDAC inhibition, including p21 up-regulation and histone H3 hyperacetylation. Oral administration of AR-42 at 50 mg/kg every other day resulted in suppression of tumor burden in AsPC-1 xenograft and KPfl/flC models by 78% and 55%, respectively. Tumor suppression was associated with HDAC inhibition, increased apoptosis, and inhibition of proliferation. AR-42 as a single agent preserved muscle size and increased grip strength in KPfl/flC mice. Finally, the combination of AR-42 and gemcitabine in transgenic mice demonstrated a significant increase in survival than either agent alone. These results suggest that AR-42 represents a therapeutically promising strategy for the treatment of pancreatic cancer. The second part was aimed at developing a novel mouse model of pancreatic cancer-induced muscle wasting. Athymic nude mice were injected orthotopically into the pancreas with 1x106 AsPC-1 or Capan-1 pancreatic tumor cells. Body weight and food consumption were measured two to three times weekly. Muscle function was analyzed by grip strength just prior to sacrifice. At 6 weeks post-injection, mice were euthanized and muscle was collected for qPCR and Western blot analysis of cachexia biomarkers. Compared to tumor-free mice, AsPC-1 and Capan-1 tumor-bearing mice had a significantly decreased percent body weight loss at day 42. Muscle weight and grip strength were significantly decreased in AsPC-1 mice relative to control mice whereas no difference was seen in Capan-1 mice. qPCR analysis of gastrocnemius muscle showed upregulation of several cachexia-associated biomarkers in AsPC-1 tumor-bearing mice, including E3 ligases Atrogin-1 and MuRF1, IL-6 receptor alpha, Stat3, and Socs3, and Western blot analysis demonstrated increased expression of phosphorylated-Stat3 and phosphorylated-NF-kB in muscle. These changes were associated with significantly greater serum levels of interleukin (IL)-6 in AsPC-1 mice versus tumor-free and Capan-1 mice. These data indicate that the AsPC-1 orthotopic model recapitulates several aspects of pancreatic cancer-induced cachexia, and represents a useful model for further therapeutic development targeting cachexia in pancreatic cancer.
Ching-Shih Chen, PhD (Advisor)
Mary-Jo Burkhard, DVM, PhD, DACVP (clinical) (Committee Member)
Thomas Ludwig, PhD (Committee Member)
Sue Knoblaugh, DVM, DACVP (anatomic) (Committee Member)
152 p.
Cellular Biology; Molecular Biology; Pharmacology
Pancreatic cancer; muscle wasting; cachexia; mouse models of pancreatic cancer-induced cachexia; AR-42; HDAC inhibitor

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Citations

  • Henderson, S. E. (2017). Translating the Anti-Tumor/Anti-Cachectic Activity of AR-42, a Novel HDAC Inhibitor, into Pancreatic Cancer Therapy [Doctoral dissertation, Ohio State University]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=osu1495801301660324

    APA Style (7th edition)

  • Henderson, Sally. Translating the Anti-Tumor/Anti-Cachectic Activity of AR-42, a Novel HDAC Inhibitor, into Pancreatic Cancer Therapy . 2017. Ohio State University, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=osu1495801301660324.

    MLA Style (8th edition)

  • Henderson, Sally. "Translating the Anti-Tumor/Anti-Cachectic Activity of AR-42, a Novel HDAC Inhibitor, into Pancreatic Cancer Therapy ." Doctoral dissertation, Ohio State University, 2017. http://rave.ohiolink.edu/etdc/view?acc_num=osu1495801301660324

    Chicago Manual of Style (17th edition)

osu1495801301660324
185
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This open access ETD is published by The Ohio State University and OhioLINK.