Aspirin-Inspired 6-O-Carboxymethyl-N-Acetylglucosamine: A potent antitumor agent with enhanced efficacy.

Aspirin, widely recognized for its anti-inflammatory and cardioprotective effects, has also shown potential as a cancer therapeutic. However, its clinical application is hindered by severe adverse effects. Here, we explore 6-O-Carboxymethyl-N-Acetylglucosamine (CM-NAG) a novel derivative of N-acetylglucosamine, designed to mimic the structural and functional properties of aspirin. CM-NAG significantly inhibits the viability of both colorectal and pancreatic cancer cells. In colorectal cancer cells, CM-NAG also suppressed migration and invasion and induced apoptosis more effectively than aspirin. Mechanistically, CM-NAG upregulated phosphoenolpyruvate carboxykinase 2 (PCK2), a key regulator of gluconeogenesis in colorectal cancer cells. In a xenograft model, CM-NAG reduced tumor size and improved histopathological outcomes, while showing no significant toxicity in major organs. The expression of PCK2 in CRC tissues was significantly lower than in cancer-adjacent tissues, according immunohistochemistry analysis. Clinical analysis revealed high PCK2 expression in colorectal cancer tissues correlates with better disease-free survival, supporting PCK2 as a promising therapeutic target. These findings suggest that CM-NAG may represent a next-generation antitumor agent with enhanced efficacy and safety compared to aspirin, offering new prospects for cancer treatment.