Abstract
Simple SummaryEpidemiological evidence suggests that breast cancer risk is lowered by Ω-3 and increased by Ω-6 polyunsaturated fatty acids (PUFAs). Paradoxically, the Ω-6 PUFA metabolite 4-hydroxynonenal (4-HNE) inhibits cancer cell growth. This duality prompted us to study whether arachidonic acid (AA) would enhance doxorubicin (dox) cytotoxicity towards breast cancer cells. We found that supplementing AA or inhibiting 4-HNE metabolism potentiated doxorubicin (dox) toxicity toward Her2-dependent breast cancer but spared myocardial cells. Our results suggest that Ω-6 PUFAs could improve outcomes of dox chemotherapy in Her2-overexpressing breast cancer.Her2-amplified breast cancers resistant to available Her2-targeted therapeutics continue to be a challenge in breast cancer therapy. Dox is the mainstay of chemotherapy of all types of breast cancer, but its usefulness is limited by cumulative cardiotoxicity. Because oxidative stress caused by dox generates the pro-apoptotic Ω-6 PUFA metabolite 4-hydroxynonenal (4-HNE), we surmised that Ω-6 PUFAs would increase the effectiveness of dox chemotherapy. Since the mercapturic acid pathway enzyme RALBP1 (also known as RLIP76 or Rlip) that limits cellular accumulation of 4-HNE also mediates dox resistance, the combination of Ω-6 PUFAs and Rlip depletion could synergistically improve the efficacy of dox. Thus, we studied the effects of the Ω-6 PUFA arachidonic acid (AA) and Rlip knockdown on the antineoplastic activity of dox towards Her2-amplified breast cancer cell lines SK-BR-3, which is sensitive to Her2 inhibitors, and AU565, which is resistant. AA increased lipid peroxidation, 4-HNE generation, apoptosis, cellular dox concentration and dox cytotoxicity in both cell lines while sparing cultured immortalized cardiomyocyte cells. The known functions of Rlip including clathrin-dependent endocytosis and dox efflux were inhibited by AA. Our results support a model in which 4-HNE generated by AA overwhelms the capacity of Rlip to defend against apoptosis caused by dox or 4-HNE. We propose that Ω-6 PUFA supplementation could improve the efficacy of dox or Rlip inhibitors for treating Her2-amplified breast cancer.
Highlights
Ω-6 and Ω-3 polyunsaturated fatty acids (PUFAs) are called essential fatty acids, required in our diets because they cannot be synthesized de novo in higher organisms.They are precursors of bioactive eicosanoids such as leukotrienes, prostaglandins, prostacyclins and hepoxilins that are key intercellular signals for regulating immunity, cell motility and inflammation [1,2,3]
Limiting the intake of Ω-6 PUFAs should aid in cancer prevention by reducing 4-HNE formation, but increasing their intake could enhance the efficacy of breast cancer treatment. We addressed this hypothesis by comparing the effects of the Ω-6 PUFA arachidonic acid (AA) and Rlip depletion on the cytotoxicity of doxorubicin, a potent generator of 4-HNE in cancer cells [60]
If the effect was due to increased 4-HNE formation, Rlip depletion should enhance the inhibitory effect of AA
Summary
Ω-6 and Ω-3 polyunsaturated fatty acids (PUFAs) are called essential fatty acids, required in our diets because they cannot be synthesized de novo in higher organisms.They are precursors of bioactive eicosanoids such as leukotrienes, prostaglandins, prostacyclins and hepoxilins that are key intercellular signals for regulating immunity, cell motility and inflammation [1,2,3]. Ω-6 and Ω-3 polyunsaturated fatty acids (PUFAs) are called essential fatty acids, required in our diets because they cannot be synthesized de novo in higher organisms. Several mechanisms have been proposed for the cancer-preventative actions of Ω-3 fatty acids, including suppression of neoplastic transformation, inhibition of cell proliferation, enhancement of apoptosis and anti-angiogenic activity. Most of these mechanisms have been directly or indirectly linked to their inhibition of the production of eicosanoids from Ω-6 fatty acids. This agrees with observations that the predominant reactive aldehyde metabolite of Ω-6 PUFA, 4-hydroxynonenal (4-HNE), is a genotoxic compound [8,9,10] that alkylates DNA bases [11,12,13] and causes DNA strand breaks to promote carcinogenesis [9,14,15,16,17]
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