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Published in final edited form as: Cancer Prev Res (Phila). 2022 Apr 1;15(4):217–223. doi: 10.1158/1940-6207.CAPR-21-0066

Celecoxib Colorectal Bioavailability and Chemopreventive Response in Familial Adenomatous Polyposis Patients

Peiying Yang 1,*, Xiangsheng Zuo 2,3, Shailesh Advani 4, Bo Wei 1, Jessica Malek 2, R Sue Day 5, Imad Shureiqi 2,3,*,#
PMCID: PMC8980107  NIHMSID: NIHMS1747623  PMID: 34610992

Abstract

Why celecoxib exerts chemopreventive activity in only some familial adenomatous polyposis (FAP) patients remains poorly understood. We conducted a phase II clinical study to identify potential predictive biomarkers for celecoxib chemopreventive activity in FAP. Twenty-seven FAP patients completed a 6-month oral course of 400 mg of celecoxib twice a day; they underwent colonoscopies before and after celecoxib treatment to assess colorectal polyp tumor burden and to obtain normal and polyp colorectal biopsies to measure celecoxib, 13-HODE, 15-HETE, 12-HETE, and LTB4 levels by LC/MS/MS. Celecoxib levels in sera from those patients were also measured before treatment and after 2, 4, and 6 months of treatment. Nineteen of the 27 patients experienced a response to celecoxib, with a ≥ 28% reduction of colonic polyp burden on the basis of a reproducible quantitative assessment of colonoscopy results. Celecoxib levels were significantly lower in polyp tissues than in normal colorectal tissues. Celecoxib levels in sera and normal colorectal tissues were correlated in patients who experienced a response to celecoxib but not in those who did not. Among the measured lipoxygenase products, only 13-HODE levels were significantly lower in polyp tissues than in normal tissues. Our findings demonstrate the differential bioavailability of celecoxib between normal and polyp tissues and its potential effects on clinical response in FAP patients.

Keywords: celecoxib, polyps, colorectal cancer, chemoprevention, lipoxygenase

INTRODUCTION

Non-steroidal anti-inflammatory drugs (NSAIDs) are a very promising class of chemopreventive agents in colorectal carcinogenesis (CRC), as shown in epidemiologic, preclinical, and clinical studies (1). Nevertheless, the estimated efficacy rate of NSAIDs in CRC chemoprevention is 50% or less (1–4). Furthermore, NSAIDs, especially COX-2 inhibitors such as celecoxib, have been associated with an increased risk of cardiovascular events (5), (6). Thus, identifying patients who might benefit from this chemopreventive approach is imperative to better tailor treatment to maximize the benefit versus the risk.

Familial adenomatous polyposis (FAP) is an autosomal dominant hereditary cancer syndrome with 100% penetrance; it is characterized by the early onset of a large number of colorectal adenomas that invariably lead to CRC development before the age of 40 years (7). Thus, the development of effective chemopreventive interventions for these patients is important. In FAP clinical trials, celecoxib reduced the colorectal adenoma burden in approximately 50% of patients (8). NSAIDs were initially believed to act by inhibiting prostaglandin synthesis; however, various reports have questioned this concept, including one showing that PGE2 inhibition is not correlated with the reduction in polyp burden by celecoxib in FAP patients (9). Thus, more predictive mechanistic biomarkers of NSAIDs’ chemopreventive effects are still needed.

Lipoxygenases (LOXs) are a class of enzymes that are involved in polyunsaturated fatty acid metabolism. Within this family, 15-lipoxygenase-1 (15-LOX-1) is the main enzyme that metabolizes linoleic acid, the predominant polyunsaturated fatty acid in the human diet, to produce 13-S-hydroxyoctadecadienoic acid (13-S-HODE), which has differential anti-tumorigenic effects compared to those of other LOX products (10). 15-LOX-1 is downregulated in human-invasive CRCs and in colorectal adenomas in FAP and non-FAP patients(11,12). Celecoxib upregulates 15-LOX-1 expression and increases 13-S-HODE production to suppress CRC in preclinical models (13). However, whether celecoxib modulates the polyunsaturated fatty acid metabolism by LOXs to exert chemopreventive effects clinically remains unclear. In the current study, we examined whether celecoxib modulates the polyunsaturated fatty acid metabolism via LOXs in the colon to affect its chemopreventive effects in FAP patients.

METHODS

Clinical study and human colonic tissue sampling

The Institutional Review Board (IRB) of The University of Texas MD Anderson Cancer Center (Houston, Texas) approved our clinical protocol (NCT00503035), which ensured that studies are conducted in accordance with the recognized ethical principles (e.g., Declaration of Helsinki, Belmont Rule, U.S. Common Rule). For all patients, we obtained an institutional IRB approved individual written informed consent from each subject before participating in the study. This single-arm celecoxib study enrolled 47 FAP patients at MD Anderson between November 2004 and May 2010. Twenty-seven patients completed the procedures required for the reported laboratory analyses. A baseline colonoscopy (or sigmoidoscopy in patients who had undergone colectomy) was performed before the initiation of celecoxib, and a follow-up colonoscopy or sigmoidoscopy was performed after celecoxib treatment. The celecoxib dose was 400 mg, given orally twice daily for 6 months. Patients’ demographic and clinical characteristics, treatment schedules, and polyp burden assessment to determine response have been described previously (14). Celecoxib levels in sera were measured and assessed prior to the initiation of the study and then after 2, 4, and 6 months of treatment at the MD Anderson diagnostic laboratory or Quest Diagnostics.

Celecoxib treatment of ApcΔ580 mice

Mouse care and experimental protocols were approved and conducted in accordance with the guidelines of the Animal Care and Use Committee of MD Anderson. ApcΔ580-flox mice were bred with CDX2-cre mice that specifically expressed Cre recombinase in the colon to generate ApcΔ580-flox(+/−); CDX2-Cre(+/−) mice [ApcΔ580(+/−), designated as ApcΔ580 mice in this study], in which one allele has an Apc codon 580 frame-shift mutation in colons.

Celecoxib powder was obtained from commercially available celecoxib capsules (200 mg/capsule, NDC 69097-421-07, Cipla USA, Inc.) and mixed with 4% carboxymethylcellulose sodium (cat. #C9481, Sigma) to create a celecoxib suspension at a concentration of 20 mg/ml. We orally administered the celecoxib suspension via gavage to 14-week-old ApcΔ580 mice with existing colon tumors (n = 6) (15) at a final dose of 200 mg/kg/day for 5 consecutive days. The mice were euthanized, and the colonic tumors and adjacent normal colonic tissues were harvested, immediately flash-frozen in liquid nitrogen, and stored in a −80°C freezer until they were analyzed.

Liquid chromatography and tandem mass spectrometry measurements (LC/MS/MS) of celecoxib levels and LOXs’ products

Lipid products and celecoxib were extracted in a manner similar to previously published methods (16). In brief, each frozen biopsy tissue sample was sectioned into 1- to 2-mm strips and were transferred to microcentrifuge tubes. An Aliquot of500 μl cold tissue homogenization buffer was then added to the samples before they were homogenized in an Ultrasonic Processor (Misonix) for 3.5 minutes (2x) at 0°C. (17). Following centrifugation at 10,000 rpm for 5 minutes at 4°C, an aliquot of 400-μl supernatant was transferred to a glass tube and 600 μl of PBS buffer (1 mM EDTA, 1% butylated hydroxytoluene and 10 μl of 12-, or 15-hydroxyeicosatetraenoic acid [12- or 15-HETE]; leukotriene B4 [LTB4]; or 13-HODE; 100 ng/ml) was added. Samples were acidified with 0.5 N HCl (pH = 3.2 to 3.3) and subjected to the extraction with 2 mL of ethyl acetate. The upper organic layer was collected and extraction was repeated two more times. The organic layers from three extractions were pooled and evaporated to dryness under a stream of nitrogen. Samples were then reconstituted in 100 μl of methanol and ammonium acetate buffer (10 mmol/L at pH 8.5; 70:30, v/v) before analyzed by liquid chromatography-tandem mass spectrometry (LC-MS/MS). The concentration of protein was measured using a Bradford protein assay (Bio-Rad). Analysis of eicosanoids was performed using a Quattro Ultima tandem mass spectrometer (Waters) equipped with an Agilent HP 1100 binary-pump HPLC inlet, as described previously (16,18). The lower limit of quantification was 0.39 ng/ml for LTB4, and 0.78 ng/ml for 12-HETE, 15-HETE, and 13-HODE. The lowest detection limit of these lipoxygenase products was 0.05–0.1 ng/ml when the signal to noise ratio was > 3. The LC/MS/MS analysis for celecoxib was carried out under a similar condition as described above for the eicosanoid analysis, with some minor changes. In brief, 10 microliters of the sample were injected to a Luna 3-μm phenyl-hexyl (2×150-mm) analytical column (Phenomenex). Celecoxib was detected and quantified by mass spectrometer using electrospray-negative ion mode and the transition m/z 380.2>316.1 for celecoxib was monitored. The results are shown as ng/mg protein.

An aliquot (100 μl) of serum was diluted with an equal volume of 10 mM ammonium acetate, pH 8.5, prior to be extracted with 4 ml of hexane: ethyl acetate (1:1, v/v). The mixture was vortexed for 5 min and then centrifuged at 4000 rpm for 5 min at 5°C. The extraction was repeated two more times, and the upper organic phase was collected, pooled, and evaporated to dryness under a stream of nitrogen. The sample was reconstituted in 200 μl of methanol: 10 mM ammonium acetate, pH 8.5 (1:1, v/v). The level of celecoxib in the samples was determined by LC/MS/MS. Serum celecoxib was quantified using authentic celecoxib standard. The results are presented as ng/ml.

To determine celecoxib levels in mouse colon tissues, we added an aliquot of 300 μl of phosphate-buffered saline to each tissue sample and homogenized the tissues in screw capped microcentrifuge tubes with ceramic beads using the Precellys tissue homogenizer (Bertin Technologies). An aliquot of 200 μL of supernatant was mixed with 1 ml of methanol, vortexed, and centrifuged at 14,800 rpm at 4°C for 10 min. The supernatant was transferred and dried with nitrogen. Samples were then reconstituted with 100 μl of methanol and 0.1% formic acid in water (1:1) prior to LC-MS/MS analysis.

The analyses for celecoxib in mouse colon tissues were performed using a 6460 Triple Quad tandem mass spectrometer (Agilent Technologies, Santa Clara, CA) equipped with an Agilent HP 1200 binary-pump HPLC inlet. Celecoxib was analyzed on a Kinetex C18 column (2.6 μm, 2.0×100 mm) (Phenomenex, Torrance, CA) using a gradient elution of 0.1% formic acids in water and 0.1% formic acid in acetonitrile. The column temperature was set at 35°C, and the flow rate was 0.4 ml/min with a 10 min of total run time. The injection volume was 5 μl. Celecoxib was detected and quantified by the mass spectrometer operated in electrospray-negative ion mode and the transition m/z 380>316 was used to monitor the celecoxib, as described previously.

Diet, supplement and medication intake

A 137-item semi-quantitative food frequency questionnaire (FFQ) was used to assess dietary and alcohol intake. The FFQ prompted participants to report their intake over the previous 6 months (19). Participant data were entered into the Food Frequency Data Entry and Analysis Program to calculate the intake of 49 nutritional components as well as individual fatty acids. Nutrient and gram weight information for the FFQ items was obtained from the Food Intake Analysis System USDA Survey Nutrient Data Base (U.S. Department of Agriculture, Agricultural Research Service, 1997; ON: Nutrient Database for Individual Intake Surveys; 1994–1996 Continuing Survey of Food Intakes by Individuals, and 1994–1996 Diet and Health Knowledge Survey [CD-ROM]). Intake of hormone replacement therapy, vitamins, and other nutritional supplements was measured using a medication questionnaire.

Statistical methods

For paired two-group comparisons (e.g., normal tissues and polyps from the same subject), we used a paired t-test. Analysis of variance (one-way) with Bonferroni adjustments was used for multiple group comparisons. All tests were two-sided, and significance was defined as P < 0.05. Data were analyzed using GraphPad Prism software 8.0.0 (GraphPad Software).

RESULTS

Patients’ demographic and clinical characteristics, treatment schedules and polyp burden assessments were described previously (14). Adherence to celecoxib intake was very high (14). Celecoxib responders were defined as those who experienced a ≥ 28% reduction in polyp tumor burden of the baseline (14) (Figure 1A). Nineteen of 27 patients were responders and 8 were non-responders. All but two of the 27 subjects continued celecoxib treatment until their blood collections and colonoscopy procedures were performed at the end of treatment. One patient in the responders’ group took the last dose 3 days prior to sample collection, and a patient in the non-responders’ group took the last dose 6 days prior to sample collection, at the endpoints described above. Unlike the other 25 subjects, these two cases had undetectable celecoxib levels in their sera on the day of colonoscopy. Their oxylipin endpoint tissue results were not included in the oxylipin analyses because they might not be reflective of celecoxib’s effects. Responders and non-responders were similar in regard to age, sex, and BMI (Supplementary Table 1). Dietary intake between responders and non-responders did not significantly differ, including total fat and arachidonic and linoleic acids (Supplementary Table 1).

Figure 1. Celecoxib levels in colorectal tissues and sera in humans and mice.

Figure 1.

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A-I. FAP patients (n = 27) received 400 mg of oral celecoxib twice per day for 6 months. Colonoscopy was performed to assess polyp burden and collect colorectal tissue samples before and 6 months after celecoxib treatment. (A) Celecoxib response statuses for each patient, based on the response cut-off of polyp tumor burden reduction by ≥ 28% from the baseline (brown dotted line). (B-D) Comparisons of celecoxib levels in sera at 2 (B), 4 (C), and 6 (D) months of celecoxib treatment in patients who did and did not experience a celecoxib response. Lines represent medians. (E-G) Comparisons of celecoxib levels in paired sera and normal colorectal tissues (E), paired sera and polyps (F), or (G) paired normal colorectal tissues and polyps at six months of celecoxib treatment. Lines represent means. Correlation analyses of celecoxib levels between sera and normal colorectal tissues at six months of celecoxib treatment in the 19 of 27 FAP patients who experienced a response (H) and in the 8 of 27 FAP patients who did not experience a response (I). (J) Comparison of celecoxib levels in normal and polyp colorectal tissue samples from ApcΔ580 mice. 14-week-old ApcΔ580 mice received celecoxib (200 mg/kg/day) via gavage for 5 consecutive days (n = 6 mice) and then were euthanized. Celecoxib levels of the paired colorectal tumor and their adjacent normal colorectal tissues are shown.

To assess whether celecoxib bioavailability affected clinical response, we measured celecoxib levels in sera and colorectal tissues. Celecoxib levels in sera were similar at 2, 4, and 6 months of celecoxib treatment between responders and non-responders (Figure 1B–D). Celecoxib levels were significantly lower in normal and polyp colorectal tissues than in their paired serum levels (Figure 1E and F). Celecoxib levels (mean ± SEM) were significantly lower in polyps (48.99 ± 16.89 ng/mg protein) than in normal colorectal tissues (134.70 ± 50.51) (Figure 1G). Celecoxib levels in normal colorectal tissues and polyps tended to be higher in the responders’ group than in the non-responders’ group, but the differences did not reach statistical significance (Supplementary Figure 1A and B). The correlation of celecoxib levels in sera and normal colorectal tissues was stronger than in sera and polyps (Supplementary Figure 1C and D). Furthermore, celecoxib levels in normal colorectal tissues were significantly correlated with those in sera in the responders (Figure 1H) but not in the non-responders (Figure 1I). Celecoxib levels were also significantly lower in colorectal tumors (1.80 ± 0.52 ng/mg protein) than in paired normal colorectal tissues (3.40 ± 0.99) in celecoxib-treated ApcΔ580 mice (Figure 1J and Supplementary Figure 2).

To evaluate celecoxib’s effects on the oxidative metabolism of LOXs-mediated linoleic and arachidonic acids, we measured major LOX oxidative products 13-HODE, 15-HETE, 12-HETE, and LTB4 levels in colorectal tissues. 13-HODE levels were higher than 15-HETE, 12-HETE, and LTB4 levels in both normal colorectal tissues and polyps (Supplementary Figures 3A and B) and higher in normal colorectal tissues than in polyps (mean ± SEM: 23.03 ± 3.57 versus 14.56 ± 1.95 ng/mg protein, Figure 2A), while 15-HETE and 12-HETE levels were similar between normal and polyps (Figure 2D and G). LTB4 was lower than the detection limit in 44%-46% of the tissue samples. The detectable LTB4 levels were similar between normal and polyps (median = 0.07 ng/mg protein for normal tissue and 0.07 ng/mg protein for polyps) (Supplementary Figure 3C).

Figure 2. Effects of celecoxib on generations of colorectal lipoxygenase products in FAP patients.

Figure 2.

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The indicated lipoxygenase products were measured by liquid chromatography/tandem mass spectrometry (LC/MS/MS) in normal tissues and polyps before and 6 months after celecoxib treatment. (A, D, G) Comparisons of 13-HODE (A), 15-HETE (D), and 12-HETE (G) levels in paired normal and polyp colorectal tissue samples from FAP patients prior to celecoxib treatment (n = 27). Lines represent means. (B, C, E, F, H and I) Comparisons of 13-HODE (B and C), 15-HETE (E and F), and 12-HETE (H and I) levels between pre- and post- 6 months of celecoxib treatment in normal and polyp colorectal tissues of FAP patients who did (n = 18) and did not (n = 7) experience a celecoxib response. Lines represent medians.

13-HODE levels after 6 months of celecoxib treatment tended to be higher than those from before treatment in both normal and polyp colorectal tissues in the responders’ group, but these differences failed to reach statistical significance (Figure 2B). In contrast, 13-HODE levels after celecoxib treatment tended to be lower than those before treatment in normal colorectal tissues and polyps from the non-responders’ group (Figure 2C). The ratios of 13-HODE levels of 6 months of celecoxib treatment over pre-celecoxib treatment were significantly higher in normal colorectal tissues in responders than in those from non-responders (P = 0.01, Supplementary Figure 4A); we also found a similar trend, although non-statistically significant, in the polyps of responders versus non-responders (P = 0.44; Supplementary Figure 4B). The levels of pre- and post-celecoxib treatments and the ratios of post- over pre- celecoxib treatment in normal colorectal tissues and polyps from responders and non-responders were similar for 15-HETE (Figure 2E and F and Supplementary Figures 4C and D), 12-HETE (Figure 2H and I, and Supplementary Figures 4E and F), and detectable LTB4 levels (Supplementary Figures 4G and H).

DISCUSSION

We found that celecoxib bioavailability was reduced in colorectal polyps. Both non-responders and responders had good celecoxib systemic bioavailability, as measured by serum levels at 2, 4, and 6 months after celecoxib treatment. However, celecoxib levels were significantly lower in polyps than in paired normal colorectal tissues in FAP patients. The lack of correlation in celecoxib levels between sera and normal colorectal tissues in non-responders further suggests that reduced bioavailability in colorectal tissues contributed to the failure of celecoxib to reduce polyp formation. Studies in ApcΔ580 mice that experimentally model human FAP similarly showed that celecoxib levels were lower in colorectal tumors than in their paired normal-appearing colorectal tissues. This observation further supports the concept that the reduction of celecoxib bioavailability limits the chemo-preventive effectiveness of celecoxib.

Celecoxib undergoes extensive hepatic metabolism in humans primarily via the cytochrome P450 2C9 (CYP2C9) enzyme to form hydroxycelecoxib, which is further oxidized to form carboxycelecoxib and then conjugated with glucuronic acid by UGT to form the 1-O-glucuronide that is excreted in feces and urine (20). CYP2C9 polymorphism significantly modulates celecoxib’s pharmacokinetics and pharmacodynamics (21). For example, 400 mg of celecoxib reduces adenoma recurrence risk more than does the 200 mg dose only in individuals with the CYP2C9*3 genotype variant, while celecoxib’s cardiovascular side effects are increased at 200 mg dose in subjects with wild-type but not in those with CYP2C9*2 or CYP2C9*3 variants (22). In our small study, we did not measure CYP2C9 genotypes because of the low frequency of these genotype variants (6%-10% in general population) (22). Nevertheless, serum celecoxib levels at the time of response assessment were similar between responders and non-responders, which strongly suggests that our response differences were unlikely to have been affected by CYP2C9 genotype variants. The differential bioavailability of celecoxib in the normal colon and colorectal polyps could be mediated by somatic CYP2C9 expression differences between normal and polyp tissues, as CYP2C9 expression levels have been reported to be higher in colon adenocarcinoma than in paired normal colonic mucosa (23). Alternatively, the differentially reduced bioavailability of celecoxib in colorectal polyps may be the result of differential vascular delivery between normal colons and polyps. In advanced cancer, reduced drug bioavailability in cancer tissues has been well described and documented to limit anti-cancer treatment activity (24), (25). Whether this principle applies to earlier stages of tumorigenesis is poorly understood. Further investigation is thus warranted to determine whether CYP2C9 is differentially expressed in polyps or whether dysfunctional vasculature in the polyps modulates celecoxib bioavailability. Meanwhile, our data demonstrate celecoxib’s differential bioavailability in colorectal polyps, suggesting that monitoring levels of anti-tumorigenic agents in tissues rather than in sera is needed for better chemopreventive response prediction.

Our results confirmed that the reduction in 13-HODE in CRC differed compared to that in other LOX products, and was unrelated to the difference in the intake of its substrate (i.e. linoleic acid) or other dietary factors (16). 13-HODE levels in normal colorectal tissues, and to a lesser degree in polyps, tended to increase in celecoxib responders after 6 months of celecoxib treatment but tended to decrease in non-responders, although these differences were statistically non-significant. Nonetheless, the changes in normal colorectal tissues’ 13-HODE levels (ratios of post- over pre-celecoxib treatment) were significantly different between responders and non-responders. Our inability to detect a statistically difference in celecoxib modulation of 13-HODE in FAP patients who experienced a response to celecoxib could be related to 1) the small sample size; and 2) low levels of celecoxib in colorectal tissues at the time of measurement (9/19 subjects in the responder group had celecoxib levels less than 50 ng/mg [approximately 0.13 μM] protein in normal colorectal tissues). These celecoxib levels are significantly lower than the lowest reported celecoxib level (12.5 μM) to induce 15-LOX-1 expression and increase 13-HODE levels in preclinical studies (13). Our findings nevertheless underscore the need to measure anti-tumorigenic drugs’ concentrations in target tissues when assessing the effects of these agents on putative biomarkers to ensure adequate drug concentrations for targeting the biomarker of interest.

One of our study limitations is that our population was restricted to FAP patients; there might be differences in celecoxib mechanisms between sporadic CRC and FAP patients. Further studies, including in patients with sporadic CRC, are needed to assess the potential mechanisms of this reduced celecoxib bioavailability to identify approaches to enhance chemo-preventive activity.

In conclusion, our findings demonstrate the need to consider the bioavailability of chemo-preventive agents in target tissues as a potential rate-limiting factor to their effectiveness and the need to identify strategies to address this resistance mechanism.

Supplementary Material

1

Prevention Relevance:

This study evaluated potential predictive biomarkers for celecoxib chemopreventive activity in FAP patients. Our findings demonstrated the differential bioavailability of celecoxib between normal and polyp tissues and its potential effects on clinical chemopreventive response in FAP patients.

ACKNOWLEDGMENTS

This work was supported by the National Cancer Institute (R01-CA106577 and R01-CA137213 to I.S., R01-CA144053 to P.Y., and R03-CA235106 to X.Z.). We acknowledge all of our patients, who contributed their time and valuable resources to this research.

Footnotes

AUTHORS’ DISCLOSURES

The authors declare no competing interests.

Supplemental information can be found online.

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Supplementary Materials

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NIHMS1747623-supplement-1.pdf (294.5KB, pdf)

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