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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

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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.

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Abbreviations

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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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.

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Author notes

  1. Changhong Yun

    Present address: Safety Assessment and Laboratory Animal Resources, Merck & Co., West Point, PA, 19486, USA

Authors and Affiliations

  1. Department of Pharmacological and Pharmaceutical Sciences, University of Houston, Houston, TX, 77204, United States

    Changhong Yun, Li Li, Taijun Yin, Katherine Shatzer, Song Gao, Ke-He Ruan & Ming Hu

  2. Center for Epigenetics and Disease Prevention, Texas A&M University, Houston, TX, 77030, USA

    Wan-Mohaiza Dashwood & Ahmet M. Ulusan

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  1. Changhong Yun
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Correspondence to Ming Hu.

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Electronic supplementary material

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Supplementary material 1 Structures of all compounds used in the experiment (TIFF 1172 kb)

Supplementary material 2 Score grades for colon endoscopy (TIFF 12897 kb)

11_2019_1300_MOESM3_ESM.tif

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

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)

Supplementary material 5 Pirc body weight (rats started the treatment at ages of 6 weeks) (TIFF 1958 kb)

Supplementary material 6 (DOCX 13 kb)

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Yun, C., Dashwood, WM., Li, L. et al. Acute changes in colonic PGE2 levels as a biomarker of efficacy after treatment of the Pirc (F344/NTac-Apc am1137) rat with celecoxib. Inflamm. Res. 69, 131–137 (2020). https://doi.org/10.1007/s00011-019-01300-5

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  • DOI: https://doi.org/10.1007/s00011-019-01300-5

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