Growth Inhibition and Induction of Apoptosis in K562 Human Chronic Leukemic Cells by abnobaVISCUM^® flaxini, Mistletoe Extracts From Ash Tree: Involvement of Activation of Caspases, Mcl-1 Down-Regulation, and ER Stress

Abstract 4418

Evidence suggests that extracts from mistletoe (Viscum album L.) have anti-cancer effects on many human cancers. Little is known about the relationship between mistletoe extracts and hematological malignancies. In this study, we investigated the effect of abnobaVISCUM^Ò Flaxini, a commercially available mistletoe extracts from ash tree, on growth of K562 human chronic leukemic cells. Results of cell count and DNA fragmentation assays demonstrated that there was strong growth suppression and induction of apoptosis in K562 cells after treatment with abnobaVISCUM^Ò Flaxini at 2 mg/ml for 8 h. Western blot and RT-PCR analyses revealed that abnobaVISCUM^Ò Flaxini treatment also led to activation of caspase-9 and -3 and PARP cleavage, but had no effect on expression of death receptor (DR)−4 and −5 in K562 cells. Expression of Bak and Bax was not changed, but that of Mcl-1 protein was strongly repressed in abnobaVISCUM^Ò Flaxini-treated K562 cells. Moreover, while treatment with abnobaVISCUM^Ò Flaxini decreased phosphorylation of ERK-1/2 and PKB, it stimulated phosphorylationof JNK-1/2 and p38 MAPK in K562 cells. Importantly, pharmacological inhibition studies demonstrated that treatment with z-VAD-fmk (a pan-caspase inhibitor), but not SP600125 (a JNK-1/2 inhibitor) or SB203580 (a p38 MAPK inhibitor), suppressed abnobaVISCUM^Ò Flaxini-induced loss of survival and apoptosis in K562 cells, and z-VAD-fmk also blocked abnobaVISCUM^Ò Flaxini-induced Mcl-1 protein down-regulation. Induction of ER stress was also seen in abnobaVISCUM^Ò Flaxini-treated K562 cells, as judged by increased phosphorylation of eIF-2a and expression of GRP78 and CHOP, three known ER stress sensors. Collectively, these findings provide the first evidence of abnobaVISCUM^Ò Flaxini-mediated anti-survival and apoptosis inducing effects on K562 cells via activation of caspases, Mcl-1 down-regulation, and triggering ER stress.