title: Phospho-Aspirin (MDC-22) Prevents Pancreatic Carcinogenesis in Mice.
abstract: Pancreatic cancer is a deadly disease with a dismal 5-year survival rate of <6%. The currently limited treatment options for pancreatic cancer underscore the need for novel chemopreventive and therapeutic agents. Accumulating evidence indicates that aspirin use is associated with a decreased risk of pancreatic cancer. However, the anticancer properties of aspirin are restricted by its gastrointestinal toxicity and its limited efficacy. Therefore, we developed phospho-aspirin (MDC-22), a novel derivative of aspirin, and evaluated its chemopreventive efficacy in preclinical models of pancreatic cancer. Phospho-aspirin inhibited the growth of human pancreatic cancer cell lines 8- to 12-fold more potently than aspirin; based on the 24-hour IC50 values. In a Panc-1 xenograft model, phospho-aspirin, at a dose of 100 mg/kg/d 5 times per week for 30 days, reduced tumor growth by 78% (P < 0.01 vs. vehicle control). Furthermore, phospho-aspirin prevented pancreatitis-accelerated acinar-to-ductal metaplasia in mice with activated Kras. In p48-Cre;Kras(G12D) mice, cerulein treatment (6 hourly injections two times per week for 3 weeks) led to a significant increase in ductal metaplasia, replacing the majority of the exocrine compartment. Administration of phospho-aspirin 100 mg/kg/day five times per week for 21 days (starting on the first day of cerulein injection) inhibited the acinar-to-ductal metaplasia, reducing it by 87% (P < 0.01, vs. cerulein-treated control). Phospho-aspirin appeared to be safe, with the animals showing no signs of toxicity during treatment. Mechanistically, phospho-aspirin inhibited EGFR activation in pancreatic cancer, an effect consistently observed in pancreatic cancer cells, primary acinar explants and in vivo In conclusion, our findings indicate that phospho-aspirin has strong anticancer efficacy in preclinical models of pancreatic cancer, warranting its further evaluation. Cancer Prev Res; 9(7); 624-34. ©2016 AACR.
authors.affiliation: Department of Medicine, Stony Brook University, Stony Brook, New York.
authors.forename: George
authors.initials: G
authors.lastname: Mattheolabakis
authors.affiliation: Department of Medicine, Stony Brook University, Stony Brook, New York.
authors.forename: Ioannis
authors.initials: I
authors.lastname: Papayannis
authors.affiliation: Department of Family, Population and Preventive Medicine, Stony Brook University, Stony Brook, New York.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Yang
authors.affiliation: Department of Family, Population and Preventive Medicine, Stony Brook University, Stony Brook, New York.
authors.forename: Brandon M
authors.initials: BM
authors.lastname: Vaeth
authors.affiliation: Department of Family, Population and Preventive Medicine, Stony Brook University, Stony Brook, New York.
authors.forename: Ruixue
authors.initials: R
authors.lastname: Wang
authors.affiliation: Department of Pathology, Stony Brook University, Stony Brook, New York.
authors.forename: Jela
authors.initials: J
authors.lastname: Bandovic
authors.affiliation: Department of Medicine, Stony Brook University, Stony Brook, New York.
authors.forename: Nengtai
authors.initials: N
authors.lastname: Ouyang
authors.affiliation: Department of Medicine, Stony Brook University, Stony Brook, New York. Medicon Pharmaceuticals Inc, Setauket, New York.
authors.forename: Basil
authors.initials: B
authors.lastname: Rigas
authors.affiliation: Department of Medicine, Stony Brook University, Stony Brook, New York. Department of Family, Population and Preventive Medicine, Stony Brook University, Stony Brook, New York. Stony Brook Cancer Center, Stony Brook University, Stony Brook, New York. Gerardo.Mackenzie@stonybrookmedicine.edu.
authors.forename: Gerardo G
authors.initials: GG
authors.lastname: Mackenzie
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001241:Aspirin / Q000031:analogs & derivatives* / Q000494:pharmacology*; D063646:Carcinogenesis / Q000187:drug effects*; D049109:Cell Proliferation / Q000187:drug effects; D018890:Chemoprevention / Q000379:methods; D005260:Female; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D008822:Mice, Transgenic; D010190:Pancreatic Neoplasms / Q000473:pathology* / Q000517:prevention & control; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D001241:Aspirin