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A Mixture of Polyunsaturated Fatty Acids ω-3 and ω-6 Reduces Melanoma Growth by Inhibiting Inflammatory Mediators in the Murine Tumor Microenvironment

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A Mixture of Polyunsaturated Fatty Acids ω-3 and ω-6 Reduces Melanoma Growth by Inhibiting Inflammatory Mediators in the Murine Tumor Microenvironment

Ewin B Almeida et al. Int J Mol Sci.

Abstract

Background: Although it has been previously demonstrated that acute inflammation can promote the tumor growth of a sub-tumorigenic dose of melanoma cells through of 5-lipoxygenase inflammatory pathway and its product leukotriene B4, and also that the peritumoral treatment with eicosapentaenoic acid and its product, leukotriene B5, reduces the tumor development, the effect of the treatment by gavage with omega-3 and omega-6 in the tumor microenvironment favorable to melanoma growth associated with acute inflammation has never been studied.

Methods: C57BL/6 mice were coinjected with 1 × 106 apoptotic cells plus 1 × 103 viable melanoma cells into the subcutaneous tissue and treated by gavage with omega-3-rich fish oil or omega-6-rich soybean oil or a mixture of these oils (1:1 ratio) during five consecutive days.

Results: The treatment by gavage with a mixture of fish and soybean oils (1:1 ratio) both reduced the melanoma growth and the levels of leukotriene B4 (LTB4), prostaglandin E2 (PGE2), PGE2/prostaglandin E3 (PGE3) ratio, and CXC ligand 1 (CXCL1) and increased the levels of interleukin 10 (IL-10) to IL-10/CXCL1 ratio in the melanoma microenvironment.

Conclusion: The oral administration of a 1:1 mixture of fish oil and soybean oil was able to alter the release of inflammatory mediators that are essential for a microenvironment favorable to the melanoma growth in mice, whereas fish oil or soybean oil alone was ineffective.

Keywords: acute inflammation; cyclooxygenase (COX); cytokines; leukotrienes; lipoxygenase (LOX); melanoma; prostaglandins.

Conflict of interest statement

No potential conflicts of interest were disclosed.

Figures

Figure 1
Figure 1
Cell viability assay. B16F10 cells were cultured with different concentrations (40, 20, 10, and 5 μL) of fish oil rich in omega-3 (A) or soybean oil rich in omega-6 (B) or a mixture of these oils in a ratio of 1:1 (C) for 48 h. The risk value α was set at 5% (p < 0.05). * p < 0.05.
Figure 2
Figure 2
Melanoma growth assay. C57BL/6 mice were coinjected with 106 B16F10 apoptotic cells plus a sub-tumorigenic dose of 103 B16F10 viable melanoma cells in a subcutaneous tissue. After the coinjection, the mice were treated by gavage during five consecutive days with fish oil rich in omega-3 or soybean oil rich in omega-6 or a mixture of these oils in a ratio of 1:1. All experiments were carried out using groups of five 6–8 week old female mice in, at least, two independent experiments, and it was considered as harboring tumors when the subcutaneous mass reached 4 mm3 (palpable tumor). The risk value α was set at 5% (p < 0.05). * p < 0.05.
Figure 3
Figure 3
Determination of inflammatory mediators. C57BL/6 mice were coinjected with 106 B16F10 apoptotic cells plus a sub-tumorigenic dose of 103 B16F10 viable melanoma cells in a subcutaneous tissue. After the coinjection, the mice were treated by gavage during five consecutive days with fish oil rich in omega-3 or soybean oil rich in omega-6 or a mixture of these oils in a ratio of 1:1. After 21 days, the tumors were removed and a homogenate was obtained to evaluate the concentration of LTB4 (A), LTB5 (B), the ratio between LTB4 and LTB5 (LTB4/LTB5) (C), prostaglandin E2 (PGE2) (D), prostaglandin E3 (PGE3) (E), and the ratio between PGE2 and PGE3 (PGE2/PGE3) (F) in the tumor microenvironment. All experiments were carried out using groups of five 6–8 week old female mice in, at least, two independent experiments. The risk value α was set at 5% (p < 0.05). ** p < 0.01, *** p < 0.001.
Figure 4
Figure 4
Determination of cytokines in vivo. C57BL/6 mice were coinjected with 106 B16F10 apoptotic cells plus a sub-tumorigenic dose of 103 B16F10 viable melanoma cells in a subcutaneous tissue. After the coinjection, the mice were treated by gavage during five consecutive days with fish oil rich in omega-3 or soybean oil rich in omega-6 or a mixture of these oils in a ratio of 1:1. After 21 days, the tumors were removed and a homogenate was obtained to evaluate the concentration of CXC ligand 1 (CXCL1) (A), interleukin 6 (IL-6) (B), IL-10 (C), the ratio between IL-10 and CXCL1 (IL-10/CXCL1) (D) and the ratio between IL-10 and IL-6 (IL-10/IL-6) (E) in the tumor microenvironment. All experiments were performed using groups of five 6–8 week old female mice in, at least, two independent experiments. The risk value α was set at 5% (p < 0.05). * p < 0.05, ** p < 0.01.
Figure 5
Figure 5
Determination of cytokines in melanoma cell culture. B16F10 cells were cultured with different concentrations (40, 20, 10, and 5 μL) of fish oil rich in omega-3 or soybean oil rich in omega-6 or a mixture of these oils in a ratio of 1:1 for 48 h to determine the concentration of IL-10 (A), IL-6 (B), and CXCL1 (C) levels. The risk value α was set at 5% (p < 0.05). * p < 0.05.
Figure 6
Figure 6
Representative illustration of the main findings of our group. In (A), the previous results published by Bachi et al. [3] are presented. In (B), the results are shown. Arachidonic acid (AA); –cyclooxygenase (COX); CXC motif chemokine ligand 1 (CXCL1) -; interleukin 10 (IL-10); eicosapentaenoic acid (EPA); –lipoxygenase (LOX); leukotriene B4 (LTB4); leukotriene B5 (LTB5); –prostaglandin E2 (PGE2); prostaglandin E3 (PGE3).

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References

    1. Balkwill F., Mantovani A. Inflammation and cancer: Back to Virchow? Lancet. 2001;357:539–545. doi: 10.1016/S0140-6736(00)04046-0. - DOI - PubMed
    1. Joyce J.A., Pollard J.W. Microenvironmental regulation of metastasis. Nat. Rev. Cancer. 2009;9:239–252. doi: 10.1038/nrc2618. - DOI - PMC - PubMed
    1. Bachi A.L.L., Kim F.J.K., Nonogaki S., Carneiro C.R.W., Lopes J.D., Jasiulionis M.G., Correa M. Leukotriene B4 Creates a Favorable Microenvironment for Murine Melanoma Growth. Mol. Cancer Res. 2009;7:1417. doi: 10.1158/1541-7786.MCR-09-0038. - DOI - PubMed
    1. Nie D., Honn K.V. Cyclooxygenase, lipoxygenase and tumor angiogenesis. Cell Mol. Life Sci. 2002;59:799–807. doi: 10.1007/s00018-002-8468-9. - DOI - PubMed
    1. Serhan C.N., Chiang N. Endogenous pro-resolving and anti-inflammatory lipid mediators: A new pharmacologic genus. Br. J. Pharmacol. 2008;153:S200–S215. doi: 10.1038/sj.bjp.0707489. - DOI - PMC - PubMed
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