Km. Anderson et al., 5-LIPOXYGENASE INHIBITORS REDUCE PANC-1 SURVIVAL - THE MODE OF CELL-DEATH AND SYNERGISM OF MK886 WITH GAMMA-LINOLENIC ACID, Anticancer research, 18(2A), 1998, pp. 791-800
The 5-lipoxygenase inhibitors ETYA, SC41661A and MK 886 reduced the pr
oliferation and viability of Panc-1 human pancreatic cancer cells. The
extent of inhibition depended upon drug concentration and with contin
ued culture, cells detached and stained with trypan blue. Although res
ults from flow cytometry were those associated with programmed cell de
ath, despite repeated attempts, no DNA laddering consistent with its l
ater stages was detected and studies with the TUNEL assay were negativ
e. Light and electron microscopy of cells cultured with SC41661A provi
ded morphologic evidence of a population of ''dark'' cells and of an i
ncompletely expressed type 1 programmed cell death including marginati
on of chromatin at the nuclear membrane and by consolidation and degen
eration of cytoplasmic organelles, along with extensive vacuolization.
Cells cultured with MK886 exhibited compact ''dark'' cells and an unu
sual cytoplasmic mode of cell death characterized by vacuolization and
widely separated smooth infernal membranes without diagnostic nuclear
changes. This is in marked contrast to the extensive type 1 PCD induc
ed by 5-lipoxygenase inhibitors cultured with human U937 monoblastoid
cells. On balance the response of Panc-1 cells to MK886 suggests expre
ssion of a valiant type 2 (autophagic) cellular suicide, although some
contribution from components of a ''cytoplasmic'' (type 3?) form of n
on-necrotic cell death may also be considered. In a European clinical
trial, gamma linolenic acid, a polyunsaturated fatty acid that generat
es 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, inc
luding 5-fluorouracil, cisplatin or gemcitabine and only somewhat sens
itive to GLA. When gamma linolenic acid was combined with MK886 the mo
re effective of the two 5-lipoxygenase inhibitors, a synergistic reduc
tion in Panc-1 cell number and viability occurred.