Increased cytosol Ca2+ and type 1 programmed cell death in Bcl-2-positive U937 but not in Bcl-2-negative PC-3 and Panc-1 cells induced by the 5-lipoxygenase inhibitor MK 886

Q3 · MEDICINE

Article

Author: Bonomi, P. ; Anderson, K. M. ; Harris, J. E. ; Jadko, S. ; Alrefai, W. A. ; Ou, D. ; Hu, Y. ; Dudeja, P. K.

MK 886, an arachidonic acid-related analog which inhibits the enzyme, 5-lipoxygenase by an indirect mechanism involving the 5-lipoxygenase activating protein, rapidly increased U937 cytosol Ca(2+), much of which localized around the cell nuclei. Five-lipoxygenase activity was not directly involved since the direct redox-dependent 5-LPOx inhibitor, SC-41661A did not increase Ca(2+). U937 cells subsequently undergo classic type 1 programmed cell death. At least initially the ionized calcium originates from internal stores. Coincident with the rise in U937 ionized calcium, MK 886 rapidly increased reactive oxygen species and reduced mitochondrial membrane potential, as judged by several fluorescent probes. The Ca(2+) response of myeloid leukemia-derived HL-60 cells to MK 886 was similar and both cell lines express Bcl-2 protein. Bcl-2-negative Panc-1 and PC-3 cells did not respond to MK 886 with a Ca(2+) signal but did develop oxidative stress and a decline in mitochondrial membrane potential; these events are thought to contribute to the inhibition of cell proliferation and induction of a type 2 PCD. In addition to its marked inhibition of Bcl-2 mRNA synthesis, an interesting hypothesis is that MK 886, serving as a low molecular weight ligand, either by direct or indirect inhibition of U937 Bcl-2 protein function, possibly related to an ion channel activity, alters the distribution of intracellular, possibly nuclear Ca(2+), thereby promoting the development of type 1 programmed cell death.

01 May 2001·Cancer LettersQ1 · MEDICINE

The mode of cell death in H-358 lung cancer cells cultured with inhibitors of 5-lipoxygenase or the free radical spin trap, NTBN

Q1 · MEDICINE

Article

Author: K.M Anderson ; P Bonomi ; D Ou ; J.E Harris ; W Jao ; S Jadko

The 5-lipoxygenase inhibitors SC41661A and MK886 with different mechanisms of action and the free radical spin trap, NTBN inhibit proliferation of the human bronchiolar lung cancer cell line NCI H-358 (5807 CRL). With continued culture, the agents induced a form of programmed cell death in which DNA laddering was not detected and ultrastructural changes were not characteristic of classic 'type 1' cellular suicide. The changes were more consistent with a type 2 cytosolic, autophagic form of PCD. MK886 induced strikingly abnormal mitochondrial morphology. Since the lipoxygenase inhibitors and NTBN induce classic type 1 PCD in U937 monoblastoid cells, these agents can activate either pathway, depending upon cell type. It is not certain whether activation of type 1 or 2 pathways depends entirely upon cell lineage and/or initiating agent, if all cells retain both pathways, and if type 1 PCD a more effective mediator of the process. These are all relevant questions for assessing the impact of PCD on malignant cell survival and considering ways in which it might be enhanced.

01 Jan 1999·Advances in Experimental Medicine and BiologyQ4 · MEDICINE

Five-Lipoxygenase Inhibitors Reduce Panc-1 Survival: Synergism of MK886 with Gamma Linolenic Acid

Q4 · MEDICINE

Article

Author: J Meng ; JE Harris ; KM Anderson ; WA Alrefai

The 5-lipoxygenase inhibitors ETYA, SC41661A and MK886 reduced the proliferation and viability of Panc-1 human pancreatic cancer cells.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 neg.Light and electron microscopy of cells cultured with SC41661A provided morphol. 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.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 enzymic program for cellular suicide by these agents.The response of Panc-1 cells to MK886 suggests the expression of a variant cytoplasmic form of non-necrotic cell death.In a European clin. 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 clin., including 5-fluorouracil, cisplatin or gemcitabine and only somewhat sensitive to gamma linolenic acid.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.

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Indication	Highest Phase	Country/Location	Organization	Date
Inflammation	Discovery	US	G.D. Searle & Co., Inc.	-
Neoplasms	Discovery	US	G.D. Searle & Co., Inc.	-

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