The anticancer effect of phospho-tyrosol-indomethacin (MPI-621), a novel phosphoderivative of indomethacin: in vitro and in vivo studies

Zhou, Dingying; Papayannis, Ioannis; Mackenzie, Gerardo G.; Alston, Ninche; Ouyang, Nengtai; Huang, Liqun; Tang, Nujiang; Wong, Chi Chun; Rigas, Basil

doi:10.1093/carcin/bgs394

Cited by 12 publications

(8 citation statements)

References 29 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Whilst conventional NSAIDs are thought to suppress carcinogenesis in part via the inhibition of cyclooxygenase-2 (32), chemical modification with the phospho-moiety abrogates their ability to inhibit this enzyme (8). Several COX-independent molecular targets of phospho-NSAIDs have emerged in recent studies, such as the epidermal growth factor receptor (23), the thioredoxin system (11), and NF-ΚB (33). …”

Section: Discussionmentioning

confidence: 99%

Phospho-NSAIDs Have Enhanced Efficacy in Mice Lacking Plasma Carboxylesterase: Implications for their Clinical Pharmacology

et al. 2014

Self Cite

View full text Add to dashboard Cite

Purpose The purpose of the study was to evaluate the metabolism, pharmacokinetics and efficacy of phospho-NSAIDs in Ces1c-knockout mice. Methods Hydrolysis of phospho-NSAIDs by Ces1c was investigated using Ces1c-overexpressing cells. The rate of phospho-NSAID hydrolysis was compared between wild-type, Ces1c+/− and Ces1c−/− mouse plasma in vitro, and the effect of plasma Ces1c on the cytotoxicity of phospho-NSAIDs was evaluated. Pharmacokinetics of phospho-sulindac was examined in wild-type and Ces1c−/− mice. The impact of Ces1c on the efficacy of phospho-sulindac was investigated using lung and pancreatic cancer models in vivo. Results Phospho-NSAIDs were extensively hydrolyzed in Ces1c-overexpressing cells. Phospho-NSAID hydrolysis in wild-type mouse plasma was 6- to 530-fold higher than that in the plasma of Ces1c−/− mice. Ces1c-expressing wild-type mouse serum attenuated the in vitro cytotoxicity of phospho-NSAIDs towards cancer cells. Pharmacokinetic studies of phospho-sulindac using wild-type and Ces1c−/− mice demonstrated 2-fold less inactivation of phospho-sulindac in the latter. Phospho-sulindac was 2-fold more efficacious in inhibiting the growth of lung and pancreatic carcinoma in Ces1c −/− mice, as compared to wild-type mice. Conclusions Our results indicate that intact phospho-NSAIDs are the pharmacologically active entities and phospho-NSAIDs are expected to be more efficacious in humans than in rodents due to their differential expression of carboxylesterases.

show abstract

Section: Discussionmentioning

confidence: 99%

Phospho-NSAIDs Have Enhanced Efficacy in Mice Lacking Plasma Carboxylesterase: Implications for their Clinical Pharmacology

et al. 2014

Self Cite

View full text Add to dashboard Cite

show abstract

“…The pegylated derivative, very resistant to hydrolysis in vivo, proved to be efficacious in CRC prevention in APC/Min mice and safe. Additional phospho-NSAIDs have shown significant anti-CRC activity; they include phospho-ibuprofen , phosphotyrosol-indomethacin (Zhou et al, 2013) and others .…”

Section: Evolving Role Of Nsaids In Colon Cancer Preventionmentioning

confidence: 99%

The Evolving Role of Nonsteroidal Anti-Inflammatory Drugs in Colon Cancer Prevention: A Cause for Optimism

Rigas

Tsioulias

2015

J Pharmacol Exp Ther

Self Cite

View full text Add to dashboard Cite

Colorectal cancer (CRC) is a serious yet preventable disease. The low acceptance and cost of colonoscopy as a screening method for CRC make chemoprevention an important option. Nonsteroidal anti-inflammatory drugs (NSAIDs), not currently recommended for CRC prevention, have the potential to evolve into the agents of choice for this indication. Here, we discuss the promise and challenge of NSAIDs for this chemopreventive application. Multiple epidemiologic studies, randomized clinical trials (RCTs) of sporadic colorectal polyp recurrence, RCTs in patients with hereditary colorectal cancer syndromes, and pooled analyses of cardiovascular-prevention RCTs linked to cancer outcomes have firmly established the ability of conventional NSAIDs to prevent CRC. NSAIDs, however, are seriously limited by their toxicity, which can become cumulative with their long-term administration for chemoprevention, whereas drug interactions in vulnerable elderly patients compound their safety. Newer, chemically modified NSAIDs offer the hope of enhanced efficacy and safety. Recent work also indicates that targeting earlier stages of colorectal carcinogenesis, such as the lower complexity aberrant crypt foci, is a promising approach that may only require relatively short use of chemopreventive agents. Drug combination approaches exemplified by sulindac plus difluoromethylornithine appear very efficacious. Identification of those at risk or most likely to benefit from a given intervention using predictive biomarkers may usher in personalized chemoprevention. Agents that offer simultaneous chemoprevention of diseases in addition to CRC, e.g., cardiovascular and/or neurodegenerative diseases, may have a much greater potential for a broad clinical application.

show abstract

“…PTI was efficacious against human colon and lung cancer in preclinical models [11]. Therefore, we examined the metabolism of PTI in human intestine, lung and kidney microsomes.…”

Section: Resultsmentioning

confidence: 99%

“…PTI was synthesized as reported [11]. IND, demethyl-IND, debenzoyl-IND, demethyldebenzoyl-IND, IND glucuronide, diisopropyl fluorophosphates (DFP), ketoconazole and quinidine were purchased from Toronto Research Chemicals (Toronto, Canada).…”

Section: Methodsmentioning

confidence: 99%

See 1 more Smart Citation

Comparative in vitro metabolism of phospho-tyrosol-indomethacin by mice, rats and humans

Xie

Zhou

Cheng

et al. 2013

Biochemical Pharmacology

Self Cite

View full text Add to dashboard Cite

Phospho-tyrosol-indomethacin (PTI; MPI 621), a novel anti-cancer agent, is more potent and safer than conventional indomethacin. Here, we show that PTI was extensively metabolized in vitro and in vivo. PTI was rapidly hydrolyzed by carboxylesterases to generate indomethacin as its major metabolite in the liver microsomes and rats. PTI additionally undergoes cytochromes P450 (CYP)-mediated hydroxylation at its tyrosol moiety and O-demethylation at its indomethacin moiety. Of the five major human CYPs, CYP3A4 and CYP2D6 catalyze the hydroxylation and O-demethylation reactions of PTI, respectively; whereas CYP1A2, 2C9 and 2C19 are inactive towards PTI. In contrast to PTI, indomethacin is primarily O-demethylated by CYP2C9, which prefers acidic substrates. The hydrolyzed and O-demethylated metabolites of PTI are further glucuronidated and sulfated, facilitating drug elimination and detoxification. We observed substantial inter-species differences in the metabolic rates of PTI. Among the liver microsomes from various species, PTI was the most rapidly hydrolyzed, hydroxylated and O-demethylated in mouse, human and rat liver microsomes, respectively. These results reflect the differential expression patterns of carboxylesterase and CYP isoforms among these species. Of the human microsomes from various tissues, PTI underwent more rapid carboxylesterase-and CYP-catalyzed reactions in liver and intestine microsomes than in kidney and lung microsomes. Together, our results establish the metabolic pathways of PTI, reveal significant inter-species differences in its metabolism, and provide insights into the underlying biochemical mechanisms.

show abstract

The anticancer effect of phospho-tyrosol-indomethacin (MPI-621), a novel phosphoderivative of indomethacin: in vitro and in vivo studies

Cited by 12 publications

References 29 publications

Phospho-NSAIDs Have Enhanced Efficacy in Mice Lacking Plasma Carboxylesterase: Implications for their Clinical Pharmacology

Phospho-NSAIDs Have Enhanced Efficacy in Mice Lacking Plasma Carboxylesterase: Implications for their Clinical Pharmacology

The Evolving Role of Nonsteroidal Anti-Inflammatory Drugs in Colon Cancer Prevention: A Cause for Optimism

Comparative in vitro metabolism of phospho-tyrosol-indomethacin by mice, rats and humans

Contact Info

Product

Resources

About