Modulating Properties of Piroxicam, Meloxicam and Oxicam Analogues against Macrophage-Associated Chemokines in Colorectal Cancer
Abstract
:1. Introduction
2. Results
2.1. MCP and MIP Expression in Colonic Adenocarcinoma Cell Lines
2.2. Effect of Oxicams on MCP and MIP Expression in Colonic Adenocarcinoma Cell Lines
2.2.1. Time-Dependent Response to Oxicams
2.2.2. Dose-Dependent Response to Oxicams
2.3. Effect of Oxicams on MCP and MIP Secretion by Caco-2 Cells
2.4. Effect of Oxicams on NAG1 Expression in Caco-2 and HCT 116 Cells
2.5. Effect of Oxicams on NAG1 Protein Expression in Caco-2, HCT 116, and HT-29 Cells
2.6. Effect of Oxicams on the Expression of NFκB-Associated Genes in Caco-2 Cells
2.7. Local Expression of MCP and MIP Chemokines in CRC Patients
2.7.1. Pairwise Analysis of MCPs and MIPs in Transformed and Non-transformed Tumor-Adjacent Colorectal Mucosa
2.7.2. Non-Paired Analysis of the MCP and MIP Expression in Tumor and Tumor-Adjacent Tissue Compared to Normal Colonic Mucosa from Non-Cancer Patients
2.8. Impact of Cancer Pathology on Chemokine Expression
2.9. Interrelationship between the Chemokine Expression in the Bowel and Circulating MCPs and MIPs
3. Discussion
4. Materials and Methods
4.1. Patients
4.1.1. Study Population
4.1.2. Biological Material
4.2. In Vitro Studies
4.2.1. Oxicams
4.2.2. Cell Cultures
4.3. Analytical Methods
4.3.1. Transcriptomic Analysis
4.3.2. Protein Analysis
4.3.3. Chemokine Profiling
4.4. Statistical Analysis
5. Conclusions
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
Sample Availability
References
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Chemokines | Gene | N | Adjacent [NRQ] | Tumor [NRQ] | Fold Change in Tumors | p Value |
---|---|---|---|---|---|---|
MCP | CCL2 | 101 | 1.44 (1.11–1.87) | 0.68 (0.50–0.91) | ↓ 2.1 (1.5–3.1) | 0.0001 |
CCL7 | 86 | 0.90 (0.70–1.17) | 0.91 (0.66–1.25) | 1 (0.7–1.4) | 0.963 | |
CCL8 | 51 | 2.13 (1.64–2.75) | 0.42 (0.25–0.71) | ↓ 5.1 (2.8–9.0) | <0.0001 | |
MIP | CCL3 | 86 | 0.82 (0.61–1.10) | 1.09 (0.74–1.60) | ↑ 1.3 (0.9–2.0) | 0.171 |
CCL4 | 101 | 0.87 (0.71–1.07) | 1.23 (0.97–1.55) | ↑ 1.4 (1.1–2.0) | 0.022 | |
CCL19 | 51 | 1.29 (0.85–1.94) | 0.58 (0.35–0.96) | ↓ 2.2 (1.3–3.8) | 0.005 | |
CXCL2 | 51 | 0.75 (0.54–1.05) | 1.50 (0.95–2.36) | ↑ 2.0 (1.3–3.10) | 0.003 |
Gene | CCL3 | CCL4 | CCL7 | CCL8 | CCL19 | CXCL2 | |
---|---|---|---|---|---|---|---|
CCL2 | N | ns | 0.78 1 | ns | 0.60 3 | ns | ns |
A | 0.30 3 | 0.54 1 | 0.36 2 | 0.35 3 | ns | 0.55 1 | |
T | 0.44 1 | 0.57 1 | 0.76 1 | 0.89 1 | 0.46 2 | 0.36 3 | |
CCL3 | N | ns | ns | ns | ns | ns | |
A | 0.44 1 | ns | ns | ns | 0.47 2 | ||
T | 0.56 1 | 0.37 2 | 0.69 1 | 0.33 4 | 0.53 1 | ||
CCL4 | N | 0.58 3 | 0.66 3 | ns | ns | ||
A | 0.25 4 | ns | ns | 0.36 3 | |||
T | 0.53 1 | 0.49 2 | 0.45 2 | ns | |||
CCL7 | N | 0.57 3 | ns | ns | |||
A | 0.27 4 | ns | 0.27 4 | ||||
T | 0.83 1 | 0.29 4 | 0.39 3 | ||||
CCL8 | N | ns | ns | ||||
A | ns | ns | |||||
T | 0.40 3 | 0.40 3 | |||||
CCL19 | N | ns | |||||
A | −0.40 3 | ||||||
T | ns |
Parameter | Characteristics | ||
---|---|---|---|
CCL2/CCL4 | CCL3/CCL7 | CCL8/CCL19/CXCL2 | |
Number of patients, n | 101 | 86 | 51 |
Sex distribution [F/M], n | 37/64 | 31/55 | 21/30 |
Age [years], mean (95% CI) | 67.4 (65.3–69.5) | 67.5 (65.3–69.7) | 67.5 (64.5–70.5) |
Cancer TNM stage [0/I/II/III/IV], n | 8/11/33/41/8 | 8/11/23/36/8 | 8/5/11/23/4 |
Depth of tumor invasion [Tis/T2/T3/T4], n | 8/18/48/27 | 8/17/38/23 | 8/8/27/8 |
Lymph node metastasis [N0/N1/N2], n | 54/26/21 | 44/22/20 | 24/14/13 |
Distant metastasis [M0/M1], n | 93/8 | 78/8 | 47/4 |
Histological grade [G1/G2/G3/x], n | 12/58/10/21 | 11/52/10/13 | 10/34/7/0 |
Primary tumor location, n: | |||
left colon | 32 | 26 | 17 |
right colon | 36 | 28 | 17 |
rectum | 33 | 32 | 17 |
Oxicam | Structure |
---|---|
Piroxicam (#6) | |
Meloxicam (#7) | |
Compound #1 | |
Compound #2 | |
Compound #3 | |
Compound #4 | |
Compound #5 |
Symbol | Encoded Protein | Sequence (5′→3′) | Size [bp] |
---|---|---|---|
PPIA1 | Peptidylprolyl isomerase A | F: ggcaaatgctggacccaacaca R: tgctggtcttgccattcctgga | 161 |
RPLP01 | Ribosomal protein, large, P0 | F: tcacaacaagcataccaagaagc R: gtatccgatgtccacaatgtcaag | 263 |
GAPDH2 | Glyceraldehyde-3-phosphate dehydrogenase | F: tagattattctctgatttggtcgtattgg R: gctcctggaagatggtgatgg | 223 |
CCL22 | Monocyte chemotactic protein (MCP)-1 | F: tctgtgcctgctgctcatag R: acttgctgctggtgattcttc | 155 |
CCL31 | Macrophage inflammatory protein (MIP)-1 α | F: actttgagacgagcagccagtg R: tttctggacccactcctcactg | 101 |
CCL41 | Macrophage inflammatory protein (MIP)-1 β | F: ggtcatacacgtactcctggac R: gcttcctcgcaactttgtggtag | 140 |
CCL71 | Monocyte chemotactic protein (MCP)-3 | F: acagaaggaccaccagtagcca R: ggtgcttcataaagtcctggacc | 117 |
CCL81 | Monocyte chemotactic protein (MCP)-2 | F: tatccagaggctggagagctac R: tggaatccctgacccatctctc | 128 |
CXCL21 | Macrophage inflammatory protein (MIP)-2 | F: ggcagaaagcttgtctcaaccc R: ctccttcaggaacagccaccaa | 127 |
CCL191 | Macrophage inflammatory protein (MIP)-3 β | F: cgtgaggaacttccactaccttc R: gtctctggatgatgcgttctacc | 131 |
NAG11 | Nonsteroidal anti-inflammatory drug-activated gene (also known as growth differentiation factor (GDF)-15 and macrophage inhibitory cytokine (MIC)-1) | F: caaccagagctgggaagattcg R: cccgagagatacgcaggtgca | 116 |
NFKBIA1 | Nuclear factor of kappa light polypeptide gene enhancer in B-cells inhibitor, alpha (IκBα) | F: tccactccatcctgaaggctac R: caaggacaccaaaagctccacg | 101 |
MYD881 | Myeloid differentiation factor 88 (MyD88) | F: gaggctgagaagcctttacagg R: gcagatgaaggcatcgaaacgc | 129 |
RELA1 | Nuclear factor of kappa light polypeptide gene enhancer in B-cells, p65 subunit | F: tgaaccgaaactctggcagctg R: catcagcttgcgaaaaggagcc | 135 |
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Lewandowska, P.; Szczuka, I.; Bednarz-Misa, I.; Szczęśniak-Sięga, B.M.; Neubauer, K.; Mierzchała-Pasierb, M.; Zawadzki, M.; Witkiewicz, W.; Krzystek-Korpacka, M. Modulating Properties of Piroxicam, Meloxicam and Oxicam Analogues against Macrophage-Associated Chemokines in Colorectal Cancer. Molecules 2021, 26, 7375. https://doi.org/10.3390/molecules26237375
Lewandowska P, Szczuka I, Bednarz-Misa I, Szczęśniak-Sięga BM, Neubauer K, Mierzchała-Pasierb M, Zawadzki M, Witkiewicz W, Krzystek-Korpacka M. Modulating Properties of Piroxicam, Meloxicam and Oxicam Analogues against Macrophage-Associated Chemokines in Colorectal Cancer. Molecules. 2021; 26(23):7375. https://doi.org/10.3390/molecules26237375
Chicago/Turabian StyleLewandowska, Paulina, Izabela Szczuka, Iwona Bednarz-Misa, Berenika M. Szczęśniak-Sięga, Katarzyna Neubauer, Magdalena Mierzchała-Pasierb, Marek Zawadzki, Wojciech Witkiewicz, and Małgorzata Krzystek-Korpacka. 2021. "Modulating Properties of Piroxicam, Meloxicam and Oxicam Analogues against Macrophage-Associated Chemokines in Colorectal Cancer" Molecules 26, no. 23: 7375. https://doi.org/10.3390/molecules26237375