Abstract
Pancreatic cancer is an aggressive malignancy that is the fourth leading cause of death worldwide. Since there is a dire need for novel and effective therapies to improve the poor survival rates of advanced pancreatic cancer patients, we analyzed the antitumor effects of OSU-A9, an indole-3-carbinol derivative, on pancreatic cancer cell lines in vitro and in vivo. OSU-A9 exhibited a stronger antitumor effect than gemcitabine on two pancreatic cancer cell lines, including gemcitabine-resistant PANC-1 cells. OSU-A9 treatment induced apoptosis, the down-regulation of Akt phosphorylation, up-regulation of p38 phosphorylation and decreased phosphorylation of JAK and STAT3. Cell migration and invasiveness assays showed that OSU-A9 reduced cancer cell aggressiveness and inhibited BxPC-3 xenograft growth in nude mice. These results suggest that OSU-A9 modulates the p38-JAK-STAT3 signaling module, thereby inducing cytotoxicity in pancreatic cancer cells. Continued evaluation of OSU-A9 as a potential therapeutic agent for pancreatic cancer thus appears warrented.
Highlights
Pancreatic cancer is an aggressive malignancy and the fourth leading cause of cancer-related deaths worldwide [1]
For gemcitabine-sensitive BxPC-3 cells, treatment with OSU-A9 for 24 h exerted a stronger inhibitory effect on cell viability compared to treatment with gemcitabine, whereas, at the later time point, the inhibitory effect of OSU-A9 was less than gemcitabine
STATs belong to a family of cytoplasmic proteins with SH2 (Src Homology-2) domains that act as signal messengers and transcriptional factors involved in cellular responses to extracellular cytokines
Summary
Pancreatic cancer is an aggressive malignancy and the fourth leading cause of cancer-related deaths worldwide [1]. Chemotherapy remains the preferred treatment modality for patients with locally advanced or metastatic pancreatic cancer, but the mix of poor response rate and short progression-free interval time results in a five-year survival rate of less than 5% [3]. Novel and effective therapeutic avenues are urgently needed for the pancreatic cancer patients. We generated the OSU-A9 derivative by performing structural optimization of I3C, which provided considerable therapeutic advantages over its parent compound in terms of anti-tumor efficacy and metabolic stability [6]. OSU-A9 was demonstrated to be effective against prostate, breast, oral, liver, and acute myeloid leukemia cancer cells in vitro and in vivo [6,7,8,9,10]. It has been shown to be effective in sensitizing hepatocellular carcinoma cells to Apo2L/TRAIL treatment [11]
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