Lipoxygenase catalyzed metabolites derived from docosahexaenoic acid are promising antitumor agents against breast cancer

Chen, Kun Ming; Thompson, Henry J.; Vandenheuvel, J; Sun, Yuan; Trushin, Neil; Aliaga, César; Gowda, Raghavendra; Amin, Shantu; Stanley, Bruce A.; Manni, Andrea; El‐Bayoumy, Karam

doi:10.1038/s41598-020-79716-x

Cited by 9 publications

(8 citation statements)

References 35 publications

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“…Numerous synthetic and natural compounds have been investigated for their anti-BC properties in various cancer cell lines [ 2 , 11 , 12 , 13 , 14 , 15 , 16 , 17 , 18 , 19 , 20 , 21 , 22 ]. However, drug resistance remains a significant hurdle to their efficacy, emphasizing the need for novel targeted therapies [ 2 , 23 ].…”

Section: Introductionmentioning

confidence: 99%

Docosahexaenoic Acid, a Key Compound for Enhancing Sensitization to Drug in Doxorubicin-Resistant MCF-7 Cell Line

et al. 2023

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Drug resistance is a well-known and significant obstacle in the battle against cancer, rendering chemotherapy treatments often ineffective. To improve the effectiveness of chemotherapy, researchers are exploring the use of natural molecules that can enhance its ability to kill cancer cells and limit their spread. Docosahexaenoic acid (DHA), a lipid found in marine fish, has been shown to enhance the cytotoxicity of various anti-cancer drugs in vitro and in vivo. While the combined use of chemotherapeutic drugs with DHA demonstrated promising preliminary results in clinical trials, there is still a significant amount of information to be discovered regarding the precise mechanism of action of DHA. As the biological pathways involved in the chemosensitization of already chemoresistant MCF-7 cells are still not entirely unraveled, in this study, we aimed to investigate whether DHA co-treatment could enhance the ability of the chemotherapy drug doxorubicin to inhibit the growth and invasion of MCF-7 breast cancer cells (MCF-7/Dox) that had become resistant to the drug. Upon treating MCF-7/Dox cells with DHA or DHA–doxorubicin, it was observed that the DHA–doxorubicin combination effectively enhanced cancer cell death by impeding in vitro propagation and invasive ability. In addition, it led to an increase in doxorubicin accumulation and triggered apoptosis by arresting the cell cycle at the G2/M phase. Other observed effects included a decrease in the multi-drug resistance (MDR) carrier P-glycoprotein (P-gp) and TG2, a tumor survival factor. Augmented quantities of molecules promoting apoptosis such as Bak1 and caspase-3 and enhanced lipid peroxidation were also detected. Our findings in the cell model suggest that DHA can be further investigated as a natural compound to be used alongside doxorubicin in the treatment of breast cancer that is unresponsive to chemotherapy.

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Section: Introductionmentioning

confidence: 99%

Docosahexaenoic Acid, a Key Compound for Enhancing Sensitization to Drug in Doxorubicin-Resistant MCF-7 Cell Line

et al. 2023

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“…DHA is known to be further metabolized within the cell by 5, 12, and 15- lipoxygenases to a number of chemical species ( Figure 2 ). As we have observed elevated concentrations of 4-OH-DHA in the plasma and tissue, as well as 4-oxo-DHA in plasma of DHA, treated animals [ 11 , 15 , 16 , 17 ], the decision was made to focus on the pathway catalyzed by the 5-lipoxygenase and that ultimately yields 4-oxo-DHA. Since our goal was to minimize the potential impact of differences among cell types in enzymatic activity relating to metabolite synthesis, 4-oxo-DHA was used as a metabolic probe for these studies.…”

Section: Resultsmentioning

confidence: 99%

“…Docosahexaenoic acid (DHA), eicosapentaenoic acid (EPA), and linoleic acid (LA) were purchased from Sigma Aldrich (St. Louis, MO, USA). 4-oxo-docosahexaenoic was synthesized as previously reported [ 11 , 12 ]. Prior to treating cells in culture each of the compounds were complexed to bovine serum albumin (BSA) to reduce toxicity associated with the detergent effects of free fatty acids.…”

Section: Methodsmentioning

confidence: 99%

Building a Foundation for Precision Onco-Nutrition: Docosahexaenoic Acid and Breast Cancer

Thompson

Neil

McGinley

et al. 2021

Cancers

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In vivo evidence of heterogeneous effects of n-3 fatty acids (N3FA) on cell signaling pathways associated with the reduced growth of breast cancer has been reported and is consistent with the expectation that N3FA will not exert uniform effects on all molecular subtypes of the disease. Similarly, available evidence indicates that many metabolites of N3FA are synthesized by mammalian cells and that they exert metabolite-specific biological activities. To begin to unravel the complex relationships among molecular subtypes and effects exerted by specific N3FA metabolites on those pathways, proof-of-concept experiments were conducted using cell lines representative of common molecular subtypes of human breast cancer. N3FA differed in anticancer activity with docosahexaenoic acid (DHA) having greater anticancer activity than eicosapentaenoic acid. 4-oxo-docosahexaenoic (4-oxo-DHA), a penultimate metabolite of 5-lipoxygenase mediated DHA metabolism, induced dose-dependent inhibition of cell number accumulation with apoptosis as a primary effector mechanism. Interrogation of protein expression data using the Ingenuity Pathway Analysis (IPA) bioinformatics platform indicated that 4-oxo-DHA differentially impacted six canonical pathways and the cellular functions they regulate across common molecular subtypes of breast cancer. This included the endocannabinoid pathway for cancer inhibition that has not been previously reported. These findings provide a rationale for juxtaposing molecular subtype targeted treatment strategies with the adjuvant use of specific N3FA metabolites as an example of precision onco-nutrition (PON) for the management and control of breast cancer.

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“…Effects of MetS on the 5-LOX products of DHA (i.e., 4-HDHA and 7-HDHA) were inconsistent with one found higher and the other lower. Of note, the biological activities of these oxylipins remain poorly described except for their binding capacity to peroxisome proliferator-activated receptor gamma (PPARγ) [ 89 , 90 ] and a potential antiangiogenic effect of 4-HDHA [ 91 ]. Lower amounts of the DGLA product 12(S)-HETrE were found in MetS participants.…”

Section: Discussionmentioning

confidence: 99%

The Plasma Oxylipin Signature Provides a Deep Phenotyping of Metabolic Syndrome Complementary to the Clinical Criteria

Dalle

Tournayre

Mainka

et al. 2022

IJMS

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Metabolic syndrome (MetS) is a complex condition encompassing a constellation of cardiometabolic abnormalities. Oxylipins are a superfamily of lipid mediators regulating many cardiometabolic functions. Plasma oxylipin signature could provide a new clinical tool to enhance the phenotyping of MetS pathophysiology. A high-throughput validated mass spectrometry method, allowing for the quantitative profiling of over 130 oxylipins, was applied to identify and validate the oxylipin signature of MetS in two independent nested case/control studies involving 476 participants. We identified an oxylipin signature of MetS (coined OxyScore), including 23 oxylipins and having high performances in classification and replicability (cross-validated AUCROC of 89%, 95% CI: 85–93% and 78%, 95% CI: 72–85% in the Discovery and Replication studies, respectively). Correlation analysis and comparison with a classification model incorporating the MetS criteria showed that the oxylipin signature brings consistent and complementary information to the clinical criteria. Being linked with the regulation of various biological processes, the candidate oxylipins provide an integrative phenotyping of MetS regarding the activation and/or negative feedback regulation of crucial molecular pathways. This may help identify patients at higher risk of cardiometabolic diseases. The oxylipin signature of patients with metabolic syndrome enhances MetS phenotyping and may ultimately help to better stratify the risk of cardiometabolic diseases.

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Lipoxygenase catalyzed metabolites derived from docosahexaenoic acid are promising antitumor agents against breast cancer

Cited by 9 publications

References 35 publications

Docosahexaenoic Acid, a Key Compound for Enhancing Sensitization to Drug in Doxorubicin-Resistant MCF-7 Cell Line

Docosahexaenoic Acid, a Key Compound for Enhancing Sensitization to Drug in Doxorubicin-Resistant MCF-7 Cell Line

Building a Foundation for Precision Onco-Nutrition: Docosahexaenoic Acid and Breast Cancer

The Plasma Oxylipin Signature Provides a Deep Phenotyping of Metabolic Syndrome Complementary to the Clinical Criteria

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