NOSH-aspirin (NBS-1120) inhibits pancreatic cancer cell growth in a xenograft mouse model: Modulation of FoxM1, p53, NF-κB, iNOS, caspase-3 and ROS.

Abstract

Pancreatic cancer has poor survival rates and largely ineffective therapies. Aspirin is the prototypical anti-cancer agent but its long-term use is associated with significant side effects. NOSH-aspirin belongs to a new class of anti-inflammatory agents that were designed to be safer alternatives by releasing nitric oxide and hydrogen sulfide. In this study we evaluated the effects of NOSH-aspirin against pancreatic cancer using cell lines and a xenograft mouse model. NOSH-aspirin inhibited growth of MIA PaCa-2 and BxPC-3 pancreatic cancer cells with IC50s of 47 ± 5, and 57 ± 4 nM, respectively, while it did not inhibit growth of a normal pancreatic epithelial cell line at these concentrations. NOSH-aspirin inhibited cell proliferation, caused G0/G1 phase cycle arrest, leading to increased apoptosis. Treated cells displayed increases in reactive oxygen species (ROS) and caspase-3 activity. In MIA PaCa-2 cell xenografts, NOSH-aspirin significantly reduced tumor growth and tumor mass. Growth inhibition was due to reduced proliferation (decreased PCNA expression) and induction of apoptosis (increased TUNEL positive cells). Expressions of ROS, iNOS, and mutated p53 were increased; while that of NF-κB and FoxM1 that were high in vehicle-treated xenografts were significantly inhibited by NOSH-aspirin. Taken together, these molecular events and signaling pathways contribute to NOSH-aspirin mediated growth inhibition and apoptotic death of pancreatic cancer cells in vitro and in vivo.

• Authors: Mitali Chattopadhyay, Ravinder Kodela, Gabriela Santiago, Thuy Tien C Le, Niharika Nath, Khosrow Kashfi
• Journal: Biochemical pharmacology (Biochem Pharmacol) Vol. 176 Pg. 113857 (06 2020) ISSN: 1873-2968 [Electronic] England
• PMID: 32061771 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)
• Copyright: Copyright © 2020 Elsevier Inc. All rights reserved.

Chemical References

• 4-(3-thioxo-3H-1,2-dithiol-5-yl)phenyl 2-((4-(nitrooxy)butanoyl)oxy)benzoate
• Disulfides
• Forkhead Box Protein M1
• NF-kappa B
• Nitrates
• Reactive Oxygen Species
• Nitric Oxide Synthase Type II
• Caspase 3
• Aspirin

Topics

• Animals
• Aspirin (analogs & derivatives, chemistry, pharmacology)
• Caspase 3 (metabolism)
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Disulfides (chemistry, pharmacology)
• Forkhead Box Protein M1 (metabolism)
• Male
• Mice, Nude
• Mice, SCID
• NF-kappa B (metabolism)
• Nitrates (chemistry, pharmacology)
• Nitric Oxide Synthase Type II (metabolism)
• Pancreatic Neoplasms (drug therapy, metabolism, pathology)
• Reactive Oxygen Species (metabolism)
• Tumor Burden (drug effects)
• Xenograft Model Antitumor Assays