Mitigating Effect of 1-Palmitoyl-2-Linoleoyl-3-Acetyl-Rac-Glycerol (PLAG) on a Murine Model of 5-Fluorouracil-Induced Hematological Toxicity
<p>1-palmitoyl-2-linoleoyl-3-acetyl-rac-glycerol (PLAG) mitigates 5-Fluorouracil (5-FU)-induced neutropenia. Mice (<span class="html-italic">n</span> = 8 males per group) were intraperitoneally injected to 100 mg/kg of 5-FU immediately followed by oral administration of 50, 100, 200, and 400mg/kg of PLAG and continuing daily to day 15. (<b>A</b>) Effect of PLAG administration on the kinetics of the absolute neutrophil counts (ANCs) after 5-FU injection for 15 days. (<b>B</b>) Individual ANC data are presented as dots on days 5, 6, and 7. * indicates negative control vs. 5-FU and # indicates 5-FU vs. 5-FU + PLAG-treated groups. */# <span class="html-italic">p</span> < 0.05, **/## <span class="html-italic">p</span> < 0.01, ***/### <span class="html-italic">p</span> < 0.001. The complete blood counts (CBCs) data are representative of five independent experiments with eight mice per group.</p> "> Figure 2
<p>PLAG mitigates 5-FU-induced monocytopenia. Mice (<span class="html-italic">n</span> = 8 males per group) were intraperitoneally injected to 100 mg/kg of 5-FU immediately followed by oral administration of 50, 100, 200, and 400 mg/kg of PLAG, continuing daily until day 15. (<b>A</b>) Effect of PLAG administration on the kinetics of peripheral monocytes after 5-FU injection for 15 days. (<b>B</b>) The peripheral monocyte counts are presented as dots on days 5, 6, and 7. The complete blood counts (CBCs) data are representative of five independent experiments with eight mice per group. * indicates negative control vs. 5-FU, and # indicates 5-FU vs. 5-FU + PLAG-treated groups. */# <span class="html-italic">p</span> < 0.05, **/## <span class="html-italic">p</span> < 0.01, ***/### <span class="html-italic">p</span> < 0.001. ns., not significant.</p> "> Figure 3
<p>PLAG prevents 5-FU-induced thrombocytopenia and thrombocytosis. Mice (<span class="html-italic">n</span> = 8 males per group) were intraperitoneally injected to 100 mg/kg of 5-FU immediately followed by oral administration of 50, 100, 200, and 400 mg/kg of PLAG, continuing daily until day 15. (<b>A</b>) Effect of PLAG administration on the kinetics of peripheral platelets after 5-FU injection for 15 days. The peripheral platelet counts are presented as dots (<b>B</b>) on days 5, 6, and 7 and (<b>C</b>) on days 10, 12, and 15. The complete blood counts (CBCs) data are representative of five independent experiments with eight mice per group. * indicates negative control vs. 5-FU and # indicates 5-FU vs. 5-FU + PLAG-treated groups. */# <span class="html-italic">p</span> < 0.05, **/## <span class="html-italic">p</span> < 0.01, ***/### <span class="html-italic">p</span> < 0.001. ns., not significant.</p> "> Figure 4
<p>Correlation between hematology and pro-inflammatory cytokine/chemokines in 5-FU-treated mice. The blood samples were harvested from mice (<span class="html-italic">n</span> = 40 males per day) on days 5, 6, and 7 after 5-FU (100 mg/kg) treatment. Correlation plot between (<b>A</b>) ANCs, (<b>B</b>) monocytes, or (<b>C</b>) platelets and pro-inflammatory cytokine/chemokines the chemokine (C–X–C motif) ligand 1 (CXCL1), CXCL2, and interleukin (IL)-6 (Pearson’s correlations).</p> "> Figure 5
<p>PLAG attenuates blood levels of 5-FU-induced pro-inflammatory cytokine/chemokines and C-reactive protein (CRP). Mice (<span class="html-italic">n</span> = 8 males per group) were intraperitoneally injected to 100 mg/kg of 5-FU immediately followed by oral administration of 50, 100, 200, and 400 mg/kg of PLAG, continuing daily until day 15. Effect of PLAG administration on the kinetics of (<b>A</b>) the chemokine (C–X–C motif) ligand 1 (CXCL1), (<b>B</b>) CXCL2, (<b>C</b>) interleukin-6 (IL-6), and (<b>D</b>) CRP in blood after 5-FU injection. Individual data of CXCL1, CXCL2, IL-6, and CRP on 0.5 day (<b>E</b>,<b>G</b>,<b>I</b>,<b>K</b>) and six days (<b>F</b>,<b>H</b>,<b>J</b>,<b>L</b>) after 5-FU injection are presented as dots. The luminex and ELISA data are representative of five independent experiments with eight mice per group. * indicates negative control vs. 5-FU and # indicates 5-FU vs. 5-FU + PLAG-treated groups. */# <span class="html-italic">p</span> < 0.05, **/## <span class="html-italic">p</span> < 0.01, ***/### <span class="html-italic">p</span> < 0.001. ns., not significant.</p> "> Figure 6
<p>Effect of PLAG, olive oil, and PLH in 5-FU-induced hematological toxicity. Mice (<span class="html-italic">n</span> = 5 males per group) were intraperitoneally injected to 100 mg/kg of 5-FU, immediately followed by oral administration of 200 mg/kg of PLAG, olive oil, or PLH, continuing daily until day 15. (<b>A</b>) The chemical structure of PLAG and PLH. The effect of PLAG, olive oil, or PLH administration on the kinetics of (<b>B</b>) ANC, (<b>C</b>) monocytes, and (<b>D</b>) platelets after 5-FU injection. The CBC data are representative of three independent experiments with five mice per group. * indicates negative control vs. 5-FU and # indicates 5-FU vs. 5-FU + PLAG-treated groups. */# <span class="html-italic">p</span> < 0.05, **/## <span class="html-italic">p</span> < 0.01, ***/### <span class="html-italic">p</span> < 0.001. ns, not significant.</p> ">
Abstract
:1. Introduction
2. Results
2.1. The Administration of PLAG Attenuates 5-FU-Induced Neutropenia
2.2. The Administration of PLAG Attenuates 5-FU-Induced Monocytopenia
2.3. The Administration of PLAG Attenuates 5-FU-Induced Aberrant Changes in Platelet Counts
2.4. Correlation Between Hematology and Pro-Inflammatory Cytokine/Chemokines
2.5. The Administration of PLAG Attenuates Blood Levels of 5-FU-Induced Pro-Inflammatory Cytokine/Chemokines and C-Reactive Protein (CRP)
2.6. Comparative Analysis between Administration of PLAG and Olive Oil in 5-FU-Induced Hematological Toxicity
3. Discussion
4. Materials and Methods
4.1. Chemicals
4.2. Animals
4.3. Establishment of a Mouse Model of 5-FU-Induced Hematological Toxicity
4.4. Measurement of Potential Biomarkers for 5-FU-Induced Hematological Toxicity
4.5. Statistical Analyses
5. Conclusions
Author Contributions
Funding
Conflicts of Interest
References
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Treatment | Mean First Day of Neutropenia (±SE, Range) | Mean Duration of Neutropenia in Days (±SE, Range) | Mean First Day of Monocytopenia (±SE, Range) | Mean Duration of Monocytopenia in Days (±SE, Range) | Mean First Day of Thrombocytopenia (±SE, Range) | Mean Duration of Thrombocytopenia in Days (±SE, Range) |
---|---|---|---|---|---|---|
Control | 4.7 ± 0.2 (3–5) | 6.0 ± 0.4 (5–7) | 3.7 ± 0.4 (3–5) | 7.5 ± 0.6 (5–9) | 4.2 ± 0.4 (3–5) | 2.1 ± 0.3 (1–3) |
PLAG 50 | 5.1 ± 0.1 (5–6) | 5.3 ± 0.3 (4–7) | 5.1 ± 0.1 (5–6) | 5.6 ± 0.4 (4–7) | 3.7 ± 0.7 (3–5) | 1.7 ± 0.3 (1–2) |
PLAG 100 | 5.0 ± 0.0 (5–5) | 4.6 ± 0.4 (2–5) | 4.2 ± 0.4 (3–5) | 4.5 ± 0.8 (2–7) | 3.0 ± 0.0 (3–3) | 2.0 ± 0.0 (2–2) |
PLAG 200 | 5.0 ± 0.0 (5–5) | 3.1 ± 0.7 (1–5) | 5.8 ± 0.2 (5–6) | 1.2 ± 0.2 (1–2) | 3.0 ± 0.0 (3–3) | 2.0 ± 0.0 (2–2) |
PLAG 400 | 4.7 ± 0.0 (3–5) | 2.9 ± 0.7 (1–5) | 6.0 ± 0.0 (6–6) | 1.0 ± 0.0 (1–1) | 3.0 ± 0.0 (3–3) | 2.0 ± 0.0 (2–2) |
Two-sided p values (control vs. PLAG 50) | 0.5333 | 0.2168 | 0.0326 * | 0.0089 ** | 0.5455 | 0.6667 |
Two-sided p values (control vs. PLAG 100) | >0.9999 | 0.0513 | 0.0131 * | 0.0006 *** | 0.0808 | 0.7394 |
Two-sided p values (control vs. PLAG 200) | >0.9999 | 0.0109 * | 0.0002 *** | 0.0003 *** | N/A | N/A |
Two-sided p values (control vs. PLAG 400) | 1 | 0.0054 ** | 0.0002 *** | 0.0003 *** | N/A | N/A |
Treatment | Number of Mice of Severe Neutropenia | Mean First Day Severe Neutropenia (±SE, Range) | Mean Duration of Severe Neutropenia (±SE, Range) |
---|---|---|---|
Control | 8/8 | 5.0 ± 0.0 (5–5) | 5.1 ± 0.5 (2–7) |
PLAG 50 | 8/8 | 5.4 ± 0.2 (5–6) | 3.2 ± 0.6 (1–5) |
PLAG 100 | 8/8 | 5.4 ± 0.2 (5–6) | 2.1 ± 0.6 (1–5) |
PLAG 200 | 0/8 | None | N/A |
PLAG 400 | 0/8 | None | N/A |
Two-sided p values (Control vs. PLAG 50) | N/A | 0.2 | 0.0177 |
Two-sided p values (Control vs. PLAG 100) | N/A | 0.2 | 0.0079 |
Two-sided p values (Control vs. PLAG 200) | N/A | N/A | N/A |
Two-sided p values (Control vs. PLAG 400) | N/A | N/A | N/A |
Treatment | Nadir of ANC (cells/μL) | Mean Number of Days to Recovery—ANC ≥ 500/μL (± SE, Range) | Nadir of Monocytes (MON) (cells/μL) | Mean Number of Days to Recovery—MON ≥ 150/μL (±SE, Range) | Nadir of Platelets (PLT) (cells/nL) | Mean Number of Days to Recovery—PLT ≥ 1000 × 103/μL (±SE, Range) |
---|---|---|---|---|---|---|
Control | 3.2 ± 1.4 | 11.0 ± 0.4 (10–12) | 2.1 ± 1.1 | 11.2 ± 0.4 (10–12) | 409.6 ± 12.2 | 8.5 ± 0.6 (7–10) |
PLAG 50 | 17.6 ± 5.2 | 10.5 ± 0.3 (10–12) | 16.4 ± 5.6 | 10.7 ± 0.4 (10–12) | 689.5 ± 28.5 | 5.7 ± 0.2 (5–7) |
PLAG 100 | 27.5 ± 6.7 | 9.6 ± 0.4 (7–10) | 32.5 ± 4.1 | 8.9 ± 0.5 (7–10) | 660.6 ± 19.8 | 6.4 ± 0.6 (5–10) |
PLAG 200 | 236.2 ± 36.4 | 8.1 ± 0.7 (6–10) | 106.2 ± 22.6 | 7.0 ± 0.0 (7–7) | 786.1 ± 37.7 | 4.9 ± 0.3 (3–6) |
PLAG 400 | 245 ± 19.8 | 8.1 ± 0.7 (6–10) | 142.5 ± 26.2 | 7.0 ± 0.0 (7–7) | 813.1 ± 48.7 | 5.4 ± 0.2 (5–6) |
Two-sided p values (control vs. PLAG 50) | 0.0123 * | 0.6084 | 0.0076 ** | 0.2104 | 0.0002 *** | 0.0008 *** |
Two-sided p values (control vs. PLAG 100) | 0.0016 ** | 0.0513 | 0.0002 *** | 0.0011 * | 0.0002 *** | 0.0194 * |
Two-sided p values (control vs. PLAG 200) | 0.0002 *** | 0.0109 * | 0.0002 *** | 0.0009 *** | 0.0002 *** | 0.0002 *** |
Two-sided p values (control vs. PLAG 400) | 0.0002 *** | 0.0109 * | 0.0002 *** | 0.0007 *** | 0.0002 *** | 0.0002 *** |
Title | Treatment | Two-Sided p Values (Control vs.) | |||||
---|---|---|---|---|---|---|---|
Control | PLAG | Olive Oil | PLH | PLAG | Olive Oil | PLH | |
Mean First Day of Neutropenia | 5.0 ± 0.0 (5–5) | 5.0 ± 0.0 (5–5) | 5.0 ± 0.0 (5–5) | 5.0 ± 0.0 (5–5) | 1 | 1 | 1 |
Mean Duration of Neutropenia | 5.0 ± 0.0 (5–5) | 2.0 ± 0.0 (2–2) | 8.0 ± 1.2 (5–10) | 7.0 ± 0.0 (7–7) | 0.06 | 0.0269 * | 0.1824 |
Number of mice of Severe Neutropenia | 5/5 | 0/5 | 5/5 | 5/5 | N/A | N/A | N/A |
Mean First Day of Severe Neutropenia | 5.0 ± 0.0 (5–5) | N/A | 5.0 ± 0.0 (5–5) | 5.0 ± 0.0 (5–5) | N/A | 1 | 1 |
Mean Duration of Severe Neutropenia | 5.0 ± 0.0 (5–5) | N/A | 5.0 ± 0.0 (5–5) | 5.0 ± 0.0 (5–5) | N/A | 1 | 1 |
Nadir of ANC (cells/μL) | 28.0 ± 7.3 | 344.0 ± 90.8 | 18.0 ± 2.0 | 8.2 ± 1.8 | 0.0008 *** | 0.9986 | 0.9896 |
Mean Number of Days to Recovery ANC ≥ 500 μL (±SE, range) | 10.0 ± 0.0 (10–10) | 7.0 ± 0.0 (7–7) | 12.4 ± 1.2 (10–15) | 12.0 ± 0.0 (12–12) | 0.0375 * | 0.0577 | 0.132 |
Mean First Day of Monocytopenia | 4.2 ± 0.5 (3–5) | 6.0 ± 1.0 (5–7) | 4.2 ± 0.5 (3–5) | 3.8 ± 0.8 (1–5) | 0.4274 | 1 | 0.9661 |
Mean Duration of Monocytopenia | 6.2 ± 0.8 (5–9) | 2.5 ± 0.5 (2–3) | 7.6 ± 1.7 (5–12) | 6.2 ± 0.5 (5–7) | 0.1327 | 0.6458 | >0.9999 |
Nadir of MON | 20.2 ± 8.2 | 198.0 ± 37.5 | 20.0 ± 3.2 | 16.0 ± 2.5 | <0.0001 *** | >0.9999 | 0.9986 |
Mean Number of Days to Recovery MON ≥ 150/μL (±SE, range) | 10.4 ± 0.4 (10–12) | 8.5 ± 1.5 (7–10) | 10.8 ± 0.5 (10–12) | 10.8 ± 0.5 (10–12) | 0.2488 | 0.9454 | 0.9454 |
Mean First Day of Thrombocytopenia | 4.6 ± 0.4 (3–5) | 3.0 ± 0.0 (3–3) | 4.6 ± 0.4 (3–5) | 4.6 ± 0.4 (3–5) | 0.3979 | >0.9999 | >0.9999 |
Mean Duration of Thrombocytopenia | 2.4 ± 0.4 (2–4) | 2.0 ± 0.0 (2–2) | 2.4 ± 0.4 (2–4) | 2.4 ± 0.4 (2–4) | 0.976 | >0.9999 | >0.9999 |
Nadir of PLT | 509.0 ± 13.2 | 868.8 ± 70.2 | 518.8 ± 50.3 | 462.8 ± 17.8 | 0.0002 *** | 0.9986 | 0.8826 |
Mean Number of Days to Recovery PLT ≥ 1000 × 103/μL (±SE, range) | 8.8 ± 0.7 (7–10) | 5.0 ± 0.0 (5–5) | 7.6 ± 0.6 (7–10) | 8.2 ± 0.7 (7–10) | 0.0048 ** | 0.5361 | 0.9013 |
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Jeong, J.; Kim, Y.-J.; Lee, D.Y.; Sohn, K.-Y.; Yoon, S.Y.; Kim, J.W. Mitigating Effect of 1-Palmitoyl-2-Linoleoyl-3-Acetyl-Rac-Glycerol (PLAG) on a Murine Model of 5-Fluorouracil-Induced Hematological Toxicity. Cancers 2019, 11, 1811. https://doi.org/10.3390/cancers11111811
Jeong J, Kim Y-J, Lee DY, Sohn K-Y, Yoon SY, Kim JW. Mitigating Effect of 1-Palmitoyl-2-Linoleoyl-3-Acetyl-Rac-Glycerol (PLAG) on a Murine Model of 5-Fluorouracil-Induced Hematological Toxicity. Cancers. 2019; 11(11):1811. https://doi.org/10.3390/cancers11111811
Chicago/Turabian StyleJeong, Jinseon, Yong-Jae Kim, Do Young Lee, Ki-Young Sohn, Sun Young Yoon, and Jae Wha Kim. 2019. "Mitigating Effect of 1-Palmitoyl-2-Linoleoyl-3-Acetyl-Rac-Glycerol (PLAG) on a Murine Model of 5-Fluorouracil-Induced Hematological Toxicity" Cancers 11, no. 11: 1811. https://doi.org/10.3390/cancers11111811