Apoptotic death of pancreatic cancer cells induced by polyunsaturated fatty acids varies with double bond number and involves an oxidative mechanism.
Polyunsaturated fatty acids (PUFAs), reported to be cytotoxic at micromolar concentrations for cancer cells in vitro and in vivo, are currently being tested in clinical trials as anti-cancer agents. This study has shown that seven PUFAs all inhibited the growth in vitro of three pancreatic cancer cell lines and the HL-60 leukaemic cell line. Five PUFAs induced cell death within 20-30 h, but two less potent PUFAs induced death between 50 and 75 h. Apoptosis was demonstrated to be the mode of cell death by light, UV fluorescence, and electron microscopy, together with studies of DNA fragmentation. In a time-course study of PUFA-treated Mia-Pa-Ca-2 cells, apoptosis accounted for an average of 80 per cent of the loss of viability, with 'secondary necrosis', a feature of late apoptosis, apparently accounting for the remainder. Correlations were found between the number of fatty acid double bonds and the proportion of cells undergoing apoptosis induced in both Mia-Pa-Ca-2 cells (R = 0.88, P = 0.0001) and HL-60 cells (R = 0.85, P = 0.0001) and inversely with the micromolar concentrations of PUFAs required for 50 per cent inhibition of growth (IC50) of Mia-Pa-Ca-2 cells (R = -0.73, P = 0.05). Cell death was preceded by progressively increasing lipid peroxidation. The extent of PUFA-induced lipid peroxidation, measured as malondialdehyde (MDA), also correlated with the proportion of apoptosis induced in Mia-Pa-Ca-2 cells (R = 0.69, P = 0.025) or HL-60 cells (R = 0.64, P = 0.043), as well as with the number of fatty acid double bonds (R = 0.82, P = 0.0015). PUFA-induced apoptosis was oxidative, being blocked by both vitamin E acetate and sodium selenite, the latter in a critically time-dependent manner. The cytotoxic effects of exposure to a PUFA and to gamma-irradiation simultaneously with, or prior to, the addition of PUFA.
University Department of Surgery, Royal Infirmary of Edinburgh NHS Trust, U.K.
R A
RA
Hawkins
K
K
Sangster
M J
MJ
Arends
D000818:Animals; D017209:Apoptosis; D018533:Biomass; D053938:DNA Fragmentation; D004281:Docosahexaenoic Acids / Q000494:pharmacology; D005231:Fatty Acids, Unsaturated / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D007942:Leukemia, Experimental / Q000473:pathology; D015227:Lipid Peroxidation; D008854:Microscopy, Electron; D008856:Microscopy, Fluorescence; D010190:Pancreatic Neoplasms / Q000378:metabolism / Q000473:pathology* / Q000648:ultrastructure; D051381:Rats; D013329:Structure-Activity Relationship; D013997:Time Factors; D014407:Tumor Cells, Cultured
D005231:Fatty Acids, Unsaturated; D004281:Docosahexaenoic Acids