Background: The anticancer properties of aspirin are restricted by its gastrointestinal toxicity and its limited\nefficacy. Therefore, we synthesized phospho-aspirin (PA-2; MDC-22), a novel derivative of aspirin, and evaluated its\nchemotherapeutic and chemopreventive efficacy in preclinical models of triple negative breast cancer (TNBC).\nMethods: Efficacy of PA-2 was evaluated in human breast cancer cells in vitro, and in orthotopic and subcutaneous\nTNBC xenografts in nude mice. Mechanistic studies were also carried out to elucidate the mechanism of action of\nPA-2.\nResults: PA-2 inhibited the growth of TNBC cells in vitro more potently than aspirin. Treatment of established\nsubcutaneous TNBC xenografts (MDA-MB-231 and BT-20) with PA-2 induced a strong growth inhibitory effect,\nresulting in tumor stasis (79% and 90% inhibition, respectively). PA-2, but not aspirin, significantly prevented\nthe development of orthotopic MDA-MB-231 xenografts (62% inhibition). Mechanistically, PA-2: 1) inhibited the\nactivation of epidermal growth factor receptor (EGFR) and suppressed its downstream signaling cascades,\nincluding PI3K/AKT/mTOR and STAT3; 2) induced acetylation of p53 at multiple lysine residues and enhanced\nits DNA binding activity, leading to cell cycle arrest; and 3) induced oxidative stress by suppressing the\nthioredoxin system, consequently inhibiting the activation of the redox sensitive transcription factor NF-?B.\nThese molecular alterations were observed in vitro and in vivo, demonstrating their relevance to the anticancer\neffect of PA-2.\nConclusions: Our findings demonstrate that PA-2 possesses potent chemotherapeutic efficacy against TNBC,\nand is also effective in its chemoprevention, warranting further evaluation as an anticancer agent.
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