Arachidonate Metabolism in Breast Cancer Cultures.

Abstract : This study was initiated based on the the fact that there has been little understanding of the role of bioactive lipids in breast cancer, an epocrine gland whose function involves lipid generation. Many of the arachidonate metabolites have been characterized as initiating cascades of other biologically active molecules such as cytokines, activation of kinases and calcium mobilization; these activators of cellular signals have even been shown to alter nuclear receptors which directly interact with DNA to have far-reaching effects on cellular functions. We have found that bioactive lipid pathways were activated by IGF-I in quiescent MCF-7 WT and multidrug-resistant breast cancer cell cultures and have proceeded to examine 6 other cell lines to verify the common pathways involving eicosanoid cascades in response to growth factors. Furthermore, we have found that diverting the above pathways with specific eicosanoid inhibitors stopped proliferation at various points in the cell cycle; thus combinations of these drugs which accumulate cells in different phases of the cell cycle effectively blocked continued cell growth and induced apoptosis. We constructed and developed new drugs, classes of free-radical scavengers, which were effective antiproliferative agents in breast cancer cultures, yet displayed low toxicity to bone marrow cultures and to mice and did not induce multidrug-resistance.