Five-lipoxygenase inhibitors reduce Panc-1 survival: synergism of MK886 with gamma linolenic acid.

Abstract

The five-lipoxygenase inhibitors ETYA, SC41661A and MK 886 reduced the proliferation and viability of Panc-1 human pancreatic cancer cells (1). The extent of inhibition depended upon drug concentration and with continued culture, cells detached and stained with trypan blue. Although results from flow cytometry were consistent with programmed cell death, despite repeated attempts, no DNA laddering characteristic of its later stages was detected, and studies with the TUNEL assay were negative. Light and electron microscopy of cells cultured with SC41661A provided morphologic evidence of an incompletely expressed type 1 programmed cell death. Cells cultured with MK886 exhibited an unusual cytoplasmic mode of cell death characterized by vacuolization and widely separated smooth internal membranes without diagnostic nuclear changes. This is in marked contrast to the extensive type 1 PCD induced by 5-lipoxygenase inhibitors cultured with human U937 monoblastoid cells (2). The incomplete destruction of chromatin and absence of a fully expressed type 1 response in SC41661A-treated Panc-1 cells implies a defective initiation and/or implementation of the enzymatic “program” for cellular suicide by these agents. The response of Panc-1 cells to MK886 suggests expression of a variant “cytoplasmic” (type 2?) form of non-necrotic cell death. In a European clinical trial, gamma linolenic acid, a polyunsaturated fatty acid that generates free radicals has been combined with 5-fluorouracil as chemotherapy for pancreatic cancer. Panc-1 cell proliferation was insensitive to inhibition by several chemotherapeutic agents employed clinically, including 5-fluorouracil, cisplatin or gemcitabine and only somewhat sensitive to GLA. When gamma linolenic acid was combined with MK886, the more effective of the two 5-lipoxygenase inhibitors, a synergistic reduction in Panc-1 cell number and viability occurred.KeywordsU937 CellHuman Pancreatic Cancer CellGamma Linolenic AcidEuropean Clinical TrialAtypical TypeThese keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.