We have recently synthesized phospho-ibuprofen (MDC-917; P-I), a safer derivative of ibuprofen, which has shown anticancer activity. We investigated its efficacy and mechanism of action in the treatment of breast cancer in preclinical models.

We evaluated the anti-breast cancer efficacy of P-I alone or incorporated into liposomes (Lipo-P-I) in human ER (+) (MCF-7) and triple-negative (ER(-), PgR(-) and HER2(-); MDA-MB231) breast cancer cell lines, as they represent the most frequent (ER(+)) and the most difficult to treat (triple-negative) subtypes of breast cancer , and their xenografts in nude mice. We assessed the effect of P-I on a) the levels of reactive oxygen nitrogen species in response to P-I using molecular probes; b) the thioredoxin system (expression and redox status of thioredoxin-1 (Trx-1) and thioredoxin reductase activity); c) cyclooxygenase 2 (COX-2), nuclear factor KB (NF-KB) and mitogen-activated protein kinase (MAPK) cell signaling; and d) the growth of xenografts with stably knocked-down Trx-1.

Compared to controls, a) P-I 400 mg/kg/day inhibited the growth of MDA-MB231 xenografts 266%; and b) P-I 300 mg/kg/day inhibited the growth of MCF-7 xenografts 51% and Lipo-P-I at the same dose 181%. In both cell lines, P-I induced oxidative stress and suppressed the Trx system (oxidized Trx-1 and decreased its expression; inhibited thioredoxin reductase activity). These changes triggered downstream redox signaling: the activity of NF-KB was suppressed and the Trx-1-ASK1 complex was dissociated, activating the p38 and JNK MAPK cascades. Trx-1 knockdown abrogated P-I's anticancer effect in vitro and in vivo.

P-I is safe and effective against breast cancer. Liposomal formulation enhances its efficacy; its effect is heavily dependent on the induction of oxidative stress and the suppression of the thioredoxin system. P-I merits further evaluation as an agent for the treatment of breast cancer.

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