ArticleThe Journal of pharmacology and experimental therapeutics2012
Carboxylesterases 1 and 2 hydrolyze phospho-nonsteroidal anti-inflammatory drugs: relevance to their pharmacological activity.
Article in The Journal of pharmacology and experimental therapeutics, 2012. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 20 papers.
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Who cites it
20 citing papers in PubMed, 44 citations in OpenAlex.
- The Antiangiogenic Effect and Ocular Pharmacology of Novel Modified Nonsteroidal Anti-Inflammatory Drugs in the Treatment of Oxygen-Induced Retinopathy.Journal of ocular pharmacology and therapeutics : the official journal of the Association for Ocular Pharmacology and Therapeutics · 2023Article
- Phosphosulindac (OXT-328) prevents and reverses chemotherapy induced peripheral neuropathy in mice.Frontiers in neuroscience · 2023Article
- Animal models of dry eye disease: Useful, varied and evolving (Review).Experimental and therapeutic medicine · 2021Review
- A pharmacokinetic-pharmacodynamic model based on multi-organ-on-a-chip for drug-drug interaction studies.Biomicrofluidics · 2020Article
- Inhibition of human carboxylesterases by ginsenosides: structure-activity relationships and inhibitory mechanism.Chinese medicine · 2019Article
- Phospho-NSAIDs have enhanced efficacy in mice lacking plasma carboxylesterase: implications for their clinical pharmacology.Pharmaceutical research · 2015Article
- Fenofibrate subcellular distribution as a rationale for the intracranial delivery through biodegradable carrier.Journal of physiology and pharmacology : an official journal of the Polish Physiological Society · 2015Article
- The evolving role of nonsteroidal anti-inflammatory drugs in colon cancer prevention: a cause for optimism.The Journal of pharmacology and experimental therapeutics · 2015Review
- The in vitro metabolism of phospho-sulindac amide, a novel potential anticancer agent.Biochemical pharmacology · 2014Article
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- Curcumin enhances the lung cancer chemopreventive efficacy of phospho-sulindac by improving its pharmacokinetics.International journal of oncology · 2013Article
- Aerosol administration of phospho-sulindac inhibits lung tumorigenesis.Molecular cancer therapeutics · 2013Article
- Topically applied phospho-sulindac hydrogel is efficacious and safe in the treatment of experimental arthritis in rats.Pharmaceutical research · 2013Article
- Comparative in vitro metabolism of phospho-tyrosol-indomethacin by mice, rats and humans.Biochemical pharmacology · 2013Article
- The anticancer effect of phospho-tyrosol-indomethacin (MPI-621), a novel phosphoderivative of indomethacin: in vitro and in vivo studies.Carcinogenesis · 2013Article
- A novel NSAID derivative, phospho-ibuprofen, prevents AOM-induced colon cancer in rats.International journal of oncology · 2013Article
- Prodrugs of nonsteroidal anti-inflammatory drugs (NSAIDs), more than meets the eye: a critical review.International journal of molecular sciences · 2012Review
- In vitro and in vivo metabolic studies of phospho-aspirin (MDC-22).Pharmaceutical research · 2012Article
- Topical phospho-sulindac (OXT-328) is effective in the treatment of non-melanoma skin cancer.International journal of oncology · 2012Article
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Authors and funding
7 authors at 1 institution in 1 country.
Funding
Abstract
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.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.