P0056 Mechanistic studies of the apoptosis-inducing activity of conjugated linolenic acid on human myeloid leukaemia cells

Abstract

Background Conjugated linolenic acids (CLN) refer to a group of positionally and geometrically conjugated trienoic isomers of the C-18 polyunsaturated fatty acid (linolenic acid), which can be isolated from various plant seed oils. Recent studies have shown that CLN isomers possess diverse physiological and pharmacological activities, including hypolipidaemic, anti-oxidative, chemopreventive and antitumour properties. However, their antitumour action mechanisms on human myeloid cells remain poorly understood. Methods We tested CLN isomers in a number of human leukaemia and lymphoma cell lines. Findings Four isomers of CLN were found to suppress the proliferation of various human myeloid leukaemia and lymphoma cell lines in a dose-dependent and time-dependent manner. The 8Z10E12Z-CLN isomer, also known as jacaric acid, is present in jacaranda seed oil and showed the most potent antiproliferative effect on human promyelocytic leukaemia HL-60 cells. This CLN isomer also potently induced apoptosis, because it induced DNA fragmentation and apoptosis in the HL-60 cells with an estimated IC50 of 2 μ mol/l at 48 h. Activation of intrinsic, but not extrinsic, apoptotic pathways by jacaric acid was shown by mitochondrial membrane depolarisation, imbalanced expression between pro-apoptotic and antiapoptotic Bcl-2 proteins, release of cytochrome c from the mitochondria to cytosol, and the differential activation of caspase-3 and caspase-9 but not caspase-8 activities in HL-60 cells. Furthermore, the jacaric acid-induced production of reactive oxygen species (ROS) and induction of DNA fragmentation in HL-60 cells were both inhibited by antioxidants. Interpretation We showed that jacaric acid might exhibit its growth-inhibitory effect on human myeloid leukaemia through triggering apoptosis in leukaemia cells. Our results suggest that jacaric acid-induced apoptosis might also be mediated through the ROS-dependent cell death pathway. More in-depth investigations are needed to show the molecular and signalling mechanisms underlying the antitumour activities of CLN isomers before they can be used for the therapeutic treatment of human myeloid leukaemia.