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Acute changes in colonic PGE2 levels as a biomarker of efficacy after treatment of the Pirc (F344/NTac-Apc am1137) rat with celecoxib

  • Changhong Yun
  • Wan-Mohaiza Dashwood
  • Li Li
  • Taijun Yin
  • Ahmet M. Ulusan
  • Katherine Shatzer
  • Song Gao
  • Ke-He Ruan
  • Ming HuEmail author
Original Research Paper
First Online:
  • 74 Downloads

Abstract

Objective

This study sought to evaluate short-term treatment with COX-2 inhibitors and acute changes in colonic PGE2 levels as predictors of long-term efficacy in a genetic model of colorectal cancer.

Methods

Celecoxib oral suspension (40 mg/kg BID) was dosed to Apc-mutant Pirc (F344/NTac-Apcam1137) rats for 4 days (short-term group), or the equivalent dose of 1500 ppm celecoxib was administered in the diet for 4 months (long-term group). Percent inhibition of colonic PGE2 was calculated, and the reduction in colonic PGE2 was assessed in relation to suppression of adenomatous colon polyps.

Results

Colonic mucosa PGE2 was fourfold higher in Pirc than in F344 wild-type rats (21 vs. 5.6 pg/mg epithelial tissue), due at least in part to higher COX-2 expression, and this was confirmed by elevated PGE2-d11 levels in Pirc colonic S9 incubations. In the 4-day study, dose-dependent reductions in PGE2 were observed in colonic epithelium (-33% (P>0.05) and -57% (P=0.0012)), after low- and high-dose celecoxib treatments of 4 mg/kg and 40 mg/kg (bid), respectively. In the 4-month study, 1500 ppm celecoxib suppressed colonic epithelium PGE2 by 43.5%, and tumor multiplicity by 80% (P<0.0015). Suppression of plasma 6-keto PGF1α also was corroborated following long-term treatment with 1500 ppm celecoxib (P<0.05).

Conclusions

Acute changes in colonic mucosa PGE2 provided a rapid means of predicting long-term chemopreventive effects from celecoxib, and might be useful for screening of new COX-2 inhibitor compounds.

Keywords

Pirc rat FAP Prostaglandin E2 Chemoprevention COX-2 inhibitor Celecoxib 

Abbreviation

AA

Arachidonic acid

APC

Adenomatous polyposis coli

COX

Cyclo-oxygenase

Coxib

COX-2 inhibitor

CRC

Colorectal cancer

FAP

Familial adenomatous polyposis

FDA

Food and Drug Administration

Pirc rat

Polyposis in the rat colon rat (F344/NTac-Apcam1137)

IC50

Half-maximal inhibitory concentration

LC–MS

Liquid chromatography–mass spectrometry

NSAID

Non-steroidal anti-inflammatory drug

PGE2

Prostaglandin E2

6-keto PGF1α

6-Keto prostaglandin F1α

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Notes

Acknowledgements

We sincerely appreciate Dr. Roderick H. Dashwood (Texas A&M University) for the manuscript reviewing, Dr. Vincent H. Tam (University of Houston) and Lawrence N. Kwong (University of Texas MD Anderson Cancer Center) for the professional advice. We thank our lab mates including Rashim Singh, Lijun Xie, Yifan Tu, Dinh Bui, Zuoxu Xie, and Lu Wang who helped us to collect the rat tissue. The work is supported by a CPRIT Grant (RP180863) and NIGMS Grant (GM-070737) to Hu.

Compliance with ethical standards

Conflict of interest

The authors declare no potential conflicts of interest.

Supplementary material

11_2019_1300_MOESM1_ESM.tif (1.1 mb)
Supplementary material 1 Structures of all compounds used in the experiment (TIFF 1172 kb)
11_2019_1300_MOESM2_ESM.tif (12.6 mb)
Supplementary material 2 Score grades for colon endoscopy (TIFF 12897 kb)
11_2019_1300_MOESM3_ESM.tif (2.6 mb)
Supplementary material 3 Structural identification of PGE2-d11. MS1 spectrum (A) and MS/MS spectrum (B) of PGE2-d11. The structure of PGE2-d11 was confirmed by the MS/MS spectrum (C) of regular PGE2 and its MS fragmentation pathway (D). (TIFF 2696 kb)
11_2019_1300_MOESM4_ESM.tif (5.3 mb)
Supplementary material 4 Celecoxib drug concentration in blood (A) and colon (B) with 4-days and 4-months treatment. The acute dose (80 mg/kg per day) and long-term dose (1500 ppm drug in the diet) of celecoxib were approximately equal. Doses were converted with the following equation commended by the WHO guidance. Similar drug distributions in blood and colon (target tissue) also evidenced the dose equivalence. In the Supplementary Figure S4A, the red line showed the average celecoxib blood concentration in steady-state with 4-days treatment (40 mg/kg. bid), while the rainbow color dots indicated the celecoxib blood concentration with 4-months feeding (1500 ppm in diet). The colon drug concentrations were almost identical with two different treatment (Supplementary Figure S4B). 1500 ppm * 0.05 = 75 mg/kg (roughly equal to 80 mg/kg). Where 1 ppm in food is equivalent to in 0.05 mg/kg bodyweight per day for the rat. Reference: Guidelines for the preparation of toxicological working papers for the Joint FAO/WHO Expert Committee on Food Additives (Geneva, December 2000) http://www.who.int/foodsafety/chem/jecfa/en/tox_guidelines.pdf (TIFF 5444 kb)
11_2019_1300_MOESM5_ESM.tif (1.9 mb)
Supplementary material 5 Pirc body weight (rats started the treatment at ages of 6 weeks) (TIFF 1958 kb)
11_2019_1300_MOESM6_ESM.docx (14 kb)
Supplementary material 6 (DOCX 13 kb)

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Copyright information

© Springer Nature Switzerland AG 2019

Authors and Affiliations

  • Changhong Yun
    • 1
    • 2
  • Wan-Mohaiza Dashwood
    • 3
  • Li Li
    • 1
  • Taijun Yin
    • 1
  • Ahmet M. Ulusan
    • 3
  • Katherine Shatzer
    • 1
  • Song Gao
    • 1
  • Ke-He Ruan
    • 1
  • Ming Hu
    • 1
    Email author
  1. 1.Department of Pharmacological and Pharmaceutical SciencesUniversity of HoustonHoustonUnited States
  2. 2.Safety Assessment and Laboratory Animal ResourcesMerck & Co.West PointUSA
  3. 3.Center for Epigenetics and Disease PreventionTexas A&M UniversityHoustonUSA

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