Abstract
ObjectivePancreatic cancer is one of the most lethal types of cancer with a 5-year survival rate of ~5%. Histone deacetylases (HDACs) participate in many cellular processes, including carcinogenesis, and pharmacological inhibition of HDACs has emerged as a potential therapeutic strategy. In this study, we explored antitumor activity of the novel HDAC inhibitor AR-42 in pancreatic cancer.MethodsHuman pancreatic cancer cell lines BxPC-3 and PANC-1 were used in this study. Real-time PCR, RT-PCR, and western blotting were employed to investigate expression of specific genes and proteins, respectively. Translocation of apoptosis-inducing factor was investigated by immunofluorescence and subcellular fractionation. The number of apoptotic cells, cell cycle stages, and reactive oxygen species (ROS) generation levels were determined by flow cytometry. Cell invasiveness was examined by the Matrigel invasion assay. Efficacy of AR-42 in vivo was evaluated by utilizing BxPC-3 xenograft mouse model.ResultsAR-42 inhibited pancreatic cancer cell proliferation by causing G2/M cell cycle arrest via regulating expression levels of genes and proteins involved in cell cycle. AR-42 also induced ROS generation and DNA damage, triggering apoptosis of pancreatic cancer cells via both caspase-3-dependent and caspase-3-independent pathways. In addition, AR-42 increased expression levels of negative regulators of p53 (miR-125b, miR-30d, and miR33), which could contribute to lower expression level of mutant p53 in pancreatic cancer cells. Cell invasion assay showed that AR-42 reduced cancer cell aggressiveness and significantly diminished BxPC-3 xenograft tumor growth in vivo.ConclusionAR-42, a novel HDAC inhibitor, inhibited pancreatic cancer cells by regulating p53 expression, inducing cell cycle arrest, particularly at the G2/M stage, and activating multiple apoptosis pathways. Additionally, AR-42 inhibited cell invasiveness and potently suppressed pancreatic cancer tumors in vivo. We conclude that by virtue of its multiple mechanisms of action, AR-42 possesses a considerable potential as an antitumor agent in pancreatic cancer.
Highlights
Pancreatic cancer is the third leading cause of cancer-related deaths in the United States [1]
AR-42 inhibited pancreatic cancer cell proliferation by causing G2/M cell cycle arrest via regulating expression levels of genes and proteins involved in cell cycle
Antitumor activity of the histone deacetylase inhibitor AR-42 could contribute to lower expression level of mutant p53 in pancreatic cancer cells
Summary
Pancreatic cancer is the third leading cause of cancer-related deaths in the United States [1]. Surgery remains the best way to treat localized disease, less than 20% of patients have operable pancreatic cancer at diagnosis. 80% of patients with localized pancreatic cancer experience recurrence within three years after surgery [2]. Chemotherapy remains the preferred treatment modality for patients with locally advanced or metastatic pancreatic cancer, but a combination of poor response rate and short progression-free interval time results in a five-year survival rate of less than 5% [3]. Histone acetylation is an important determinant of gene expression. Histone deacetylases (HDACs) are enzymes that determine acetylation status of histones, thereby affecting chromatin structure and regulating the expression and activity of numerous proteins involved in both cancer initiation and cancer progression [4,5,6]. HDACis can block cell proliferation, promote differentiation, and induce apoptosis, i.e., phenomena that impede growth of cancer cells
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