Identification of a novel class of anti-inflammatory compounds with anti-tumor activity in colorectal and lung cancers

Hui Hua Chang, Zuohe Song, Lee Wisner, Tina Tripp, Vijay Gokhale, Emmanuelle Meuillet

Research output: Contribution to journalArticle

7 Citations (Scopus)

Abstract

Summary: Chronic inflammation is associated with 25% of all cancers. In the inflammation-cancer axis, prostaglandin E2 (PGE2) is one of the major players. PGE2 synthases (PGES) are the enzymes downstream of the cyclooxygenases (COXs) in the PGE2 biosynthesis pathway. Microsomal prostaglandin E2 synthase 1 (mPGES-1) is inducible by pro-inflammatory stimuli and constitutively expressed in a variety of cancers. The potential role for this enzyme in tumorigenesis has been reported and mPGES-1 represents a novel therapeutic target for cancers. In order to identify novel small molecule inhibitors of mPGES-1, we screened the ChemBridge library and identified 13 compounds as potential hits. These compounds were tested for their ability to bind directly to the enzyme using surface plasmon resonance spectroscopy and to decrease cytokine-stimulated PGE2 production in various cancer cell lines. We demonstrate that the compound PGE0001 (ChemBridge ID number 5654455) binds to human mPGES-1 recombinant protein with good affinity (KD=21.3±7.8 μM). PGE0001 reduces IL-1β-induced PGE2 release in human HCA-7 colon and A549 lung cancer cell lines with EC50 in the sub-micromolar range. Although PGE0001 may have alternative targets based on the results from in vitro assays, it shows promising effects in vivo. PGE0001 exhibits significant anti-tumor activity in SW837 rectum and A549 lung cancer xenografts in SCID mice. Single injection i.p. of PGE0001 at 100 mg/kg decreases serum PGE2 levels in mice within 5 h. In summary, our data suggest that the identified compound PGE0001 exerts anti-tumor activity via the inhibition of the PGE2 synthesis pathway.

Original languageEnglish (US)
Pages (from-to)1865-1877
Number of pages13
JournalInvestigational New Drugs
Volume30
Issue number5
DOIs
StatePublished - Oct 2012

Fingerprint

Colorectal Neoplasms
Lung Neoplasms
Dinoprostone
Anti-Inflammatory Agents
Neoplasms
Enzymes
Inflammation
Cell Line
SCID Mice
Surface Plasmon Resonance
Prostaglandin-Endoperoxide Synthases
Interleukin-1
Recombinant Proteins
Rectum
Heterografts
Libraries
Spectrum Analysis
Colon
Carcinogenesis
Prostaglandin-E Synthases

Keywords

  • Anti-tumor
  • Cancer
  • Drug design
  • Inflammation
  • Prostaglandin E

ASJC Scopus subject areas

  • Pharmacology
  • Pharmacology (medical)
  • Oncology

Cite this

Identification of a novel class of anti-inflammatory compounds with anti-tumor activity in colorectal and lung cancers. / Chang, Hui Hua; Song, Zuohe; Wisner, Lee; Tripp, Tina; Gokhale, Vijay; Meuillet, Emmanuelle.

In: Investigational New Drugs, Vol. 30, No. 5, 10.2012, p. 1865-1877.

Research output: Contribution to journalArticle

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AB - Summary: Chronic inflammation is associated with 25% of all cancers. In the inflammation-cancer axis, prostaglandin E2 (PGE2) is one of the major players. PGE2 synthases (PGES) are the enzymes downstream of the cyclooxygenases (COXs) in the PGE2 biosynthesis pathway. Microsomal prostaglandin E2 synthase 1 (mPGES-1) is inducible by pro-inflammatory stimuli and constitutively expressed in a variety of cancers. The potential role for this enzyme in tumorigenesis has been reported and mPGES-1 represents a novel therapeutic target for cancers. In order to identify novel small molecule inhibitors of mPGES-1, we screened the ChemBridge library and identified 13 compounds as potential hits. These compounds were tested for their ability to bind directly to the enzyme using surface plasmon resonance spectroscopy and to decrease cytokine-stimulated PGE2 production in various cancer cell lines. We demonstrate that the compound PGE0001 (ChemBridge ID number 5654455) binds to human mPGES-1 recombinant protein with good affinity (KD=21.3±7.8 μM). PGE0001 reduces IL-1β-induced PGE2 release in human HCA-7 colon and A549 lung cancer cell lines with EC50 in the sub-micromolar range. Although PGE0001 may have alternative targets based on the results from in vitro assays, it shows promising effects in vivo. PGE0001 exhibits significant anti-tumor activity in SW837 rectum and A549 lung cancer xenografts in SCID mice. Single injection i.p. of PGE0001 at 100 mg/kg decreases serum PGE2 levels in mice within 5 h. In summary, our data suggest that the identified compound PGE0001 exerts anti-tumor activity via the inhibition of the PGE2 synthesis pathway.

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