Phospho-aspirin (MDC-22) prevents pancreatic carcinogenesis in mice
Menée sur un modèle murin, cette étude met en évidence l'effet chimiopréventif d'un dérivé phosphoré de l'aspirine sur la carcinogenèse du pancréas
Pancreatic cancer (PC) is a deadly disease with a dismal 5-year survival rate of <6%. The currently limited treatment options for PC underscore the need for novel chemopreventive and therapeutic agents. Accumulating evidence indicates that aspirin use is associated with a decreased risk of PC. However, the anticancer properties of aspirin are restricted by its gastrointestinal toxicity and its limited efficacy. Therefore, we developed phospho-aspirin (PA; MDC-22), a novel derivative of aspirin, and evaluated its chemopreventive efficacy in preclinical models of PC. PA inhibited the growth of human PC cell lines 8-12 fold more potently than aspirin; based on the 24-h IC50 values. In a Panc-1 xenograft model, PA, at a dose of 100 mg/kg/d x5/wk for 30 days, reduced tumor growth by 78% (p<0.01 vs vehicle control). Furthermore, PA prevented pancreatitis-accelerated acinar-to-ductal metaplasia in mice with activated Kras. In p48-Cre;KrasG12D mice, cerulein treatment (6 hourly injections 2x/wk x 3 wks) led to a significant increase in ductal metaplasia, replacing the majority of the exocrine compartment. Administration of PA 100 mg/kg/d x5/wk 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). PA appeared to be safe, with the animals showing no signs of toxicity during treatment. Mechanistically, PA inhibited EGFR activation in PC, an effect consistently observed in PC cells, primary acinar explants and in vivo. In conclusion, our findings indicate that PA has strong anticancer efficacy in preclinical models of PC, warranting its further evaluation.