oxt-328 and bis(4-nitrophenyl)phosphate

Phospho-nonsteroidal anti-inflammatory drugs (phospho-NSAIDs) are novel NSAID derivatives with improved anticancer activity and reduced side effects in preclinical models. Here, we studied the metabolism of phospho-NSAIDs by carboxylesterases and assessed the impact of carboxylesterases on the anticancer activity of phospho-NSAIDs in vitro and in vivo. The expression of human liver carboxylesterase (CES1) and intestinal carboxylesterase (CES2) in human embryonic kidney 293 cells resulted in the rapid intracellular hydrolysis of phospho-NSAIDs. Kinetic analysis revealed that CES1 is more active in the hydrolysis of phospho-sulindac, phospho-ibuprofen, phospho-naproxen, phospho-indomethacin, and phospho-tyrosol-indomethacin that possessed a bulky acyl moiety, whereas the phospho-aspirins are preferentially hydrolyzed by CES2. Carboxylesterase expression leads to a significant attenuation of the in vitro cytotoxicity of phospho-NSAIDs, suggesting that the integrity of the drug is critical for anticancer activity. Benzil and bis-p-nitrophenyl phosphate (BNPP), two carboxylesterase inhibitors, abrogated the effect of carboxylesterases and resensitized carboxylesterase-expressing cells to the potent cytotoxic effects of phospho-NSAIDs. In mice, coadministration of phospho-sulindac and BNPP partially protected the former from esterase-mediated hydrolysis, and this combination more effectively inhibited the growth of AGS human gastric xenografts in nude mice (57%) compared with phospho-sulindac alone (28%) (p = 0.037). Our results show that carboxylesterase mediates that metabolic inactivation of phospho-NSAIDs, and the inhibition of carboxylesterases improves the efficacy of phospho-NSAIDs in vitro and in vivo.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Aspirin; Carboxylesterase; Carboxylic Ester Hydrolases; Cell Line, Tumor; Cell Survival; Drug Interactions; Drug Therapy, Combination; Enzyme Inhibitors; Female; HEK293 Cells; Humans; Hydrolysis; Ibuprofen; Indomethacin; Inhibitory Concentration 50; Kinetics; Mice; Mice, Inbred BALB C; Mice, Nude; Naproxen; Nitrophenols; Organophosphates; Organophosphorus Compounds; Phenylglyoxal; Stomach Neoplasms; Sulindac; Transfection; Valproic Acid; Xenograft Model Antitumor Assays