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.