Suppression of Tumor Growth and Muscle Wasting in a Transgenic Mouse Model of Pancreatic Cancer by the Novel Histone Deacetylase Inhibitor AR-42

Abstract

PURPOSE: Pancreatic ductal adenocarcinoma (PDAC) is the third leading cause of cancer death in the United States. This study was aimed at evaluating the efficacy of AR-42 (formerly OSU-HDAC42), a novel histone deacetylase (HDAC) inhibitor currently in clinical trials, in suppressing tumor growth and/or cancer-induced muscle wasting in murine models of PDAC. EXPERIMENTAL DESIGN: The in vitro antiproliferative activity of AR-42 was evaluated in six human pancreatic cancer cell lines (AsPC-1, COLO-357, PANC-1, MiaPaCa-2, BxPC-3, SW1990). 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. RESULTS: 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, which was associated with the hallmark features of HDAC inhibition, including p21 upregulation and histone H3 hyperacetylation. Oral administration of AR-42 at 50 mg/kg every other day resulted in suppression of tumor burden in the AsPC-1 xenograft and KPfl/flC models by 78% and 55%, respectively, at the end of treatment. Tumor suppression was associated with HDAC inhibition, increased apoptosis, and inhibition of proliferation. Additionally, 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. CONCLUSIONS: These results suggest that AR-42 represents a therapeutically promising strategy for the treatment of pancreatic cancer.

New developments in investigational HDAC inhibitors for the potential multimodal treatment of cachexia

“…In agreement with the data reported above, administration of the novel HDAC inhibitor AR-42 to mice bearing the C26 tumor or the Lewis lung carcinoma (LLC) improves muscle wasting in the absence of decreased tumor burden [73]. A similar improvement of muscle mass depletion has also been reported in a KP fl/fl C transgenic model of pancreatic cancer, however such protection appears associated with significant reduction of tumor mass [70].…”

DNA–SWCNT Biosensors Allow Real-Time Monitoring of Therapeutic Responses in Pancreatic Ductal Adenocarcinoma

“…One day after the second survival surgery, each mouse was treated with a 40 mg/kg dose of gemcitabine for three days (42). In agreement with previous studies from our laboratory and others, gemcitabine at this dose was effective enough and started killing the tumor cells in vivo, hence predicting elevation of the H 2 O 2 level in the TME (43).…”

Novel histone deacetylase inhibitor AR-42 exhibits antitumor activity in pancreatic cancer cells by affecting multiple biochemical pathways

“…Cytotoxicity of AR-42 in six human pancreatic cancer cell lines (AsPC-1, SW1990, BxPC-3, COLO-357, MiaPaCa-2, and PANC-1) has been evaluated previously [ 22 ]. In our study, we used gemcitabine-responsive BxPC-3 and resistant PANC-1 cell lines as our testing model to examine the cell viability by the MTT assays ( S1 Fig ).…”