Abstract
BackgroundArachidonate metabolites are important regulators of human breast cancer cells. Production of bioactive lipids are frequently initiated by the enzyme phospholipase A2 which releases arachidonic acid (AA) that is rapidly metabolized by cyclooxygenases (COX) or lipoxygenases (LO) to other highly potent lipids.MethodsIn this study we screened a number of inhibitors which blocked specific pathways of AA metabolism for their antiproliferative activity on MCF-7 wild type and MCF-7 ADR drug resistant breast cancer cells. The toxicity of these inhibitors was further tested on human bone marrow cell proliferation.ResultsInhibitors of LO pathways (specifically the 5-LO pathway) were most effective in blocking proliferation. Inhibitors of platelet activating factor, a byproduct of arachidonate release, were also effective antiproliferative agents. Curcumin, an inhibitor of both COX and LO pathways of eicosanoid metabolism, was 12-fold more effective in blocking proliferation of the MCF-7 ADRs cells compared to MCF-7 wild type (WT) cells. These inhibitors that effectively blocked the proliferation of breast cancer cells showed varying degrees of toxicity to cultures of human bone marrow cells. We observed greater toxicity to bone marrow cells with inhibitors that interfere with the utilization of AA in contrast to those which block utilization of its downstream metabolites. MK-591, MK-886, PCA-4248, and AA-861 blocked proliferation of breast cancer cells but showed no toxicity to bone marrow cells.ConclusionThese inhibitors were effective in blocking the proliferation of breast cancer cells and may be potentially useful in human breast cancer therapy.
Highlights
Arachidonate metabolites are important regulators of human breast cancer cells
arachidonic acid (AA) is metabolized through the cyclooxygenase pathway, which results in prostaglandin production or through the 5-lipoxygenase (5-LO) pathway, which results in the production of leukotriene [8]
We show that inhibitors of the 5-LO pathway can block growth of breast cancer cells, especially the drug resistant MCF-7 ADR line very effectively
Summary
Arachidonate metabolites are important regulators of human breast cancer cells. Production of bioactive lipids are frequently initiated by the enzyme phospholipase A2 which releases arachidonic acid (AA) that is rapidly metabolized by cyclooxygenases (COX) or lipoxygenases (LO) to other highly potent lipids. Various studies have suggested dietary fat content, especially polyunsaturated fatty acids, promotes tumor growth by increasing synthesis of eicosanoids, arachidonic acid (AA) products [1,2,3,4]. AA is metabolized through the cyclooxygenase pathway, which results in prostaglandin production or through the 5-lipoxygenase (5-LO) pathway, which results in the production of leukotriene [8] Both prostaglandins and leukotrienes directly stimulate the growth of malignant cells [9,10,11]
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