Dasatinib is an inhibitor of Src that has anti‐tumour effects on many haematological and solid cancers. However, the anti‐tumour effects of dasatinib on human oral cancers remain unclear. In this study, we investigated the effects of dasatinib on different types of human oral cancer cells: the non‐tumorigenic YD‐8 and YD‐38 and the tumorigenic YD‐10B and HSC‐3 cells. Strikingly, dasatinib at 10 µM strongly suppressed the growth and induced apoptosis of YD‐38 cells and inhibited the phosphorylation of Src, EGFR, STAT‐3, STAT‐5, PKB and ERK‐1/2. In contrast, knockdown of Src blocked the phosphorylation of EGFR, STAT‐5, PKB and ERK‐1/2, but not STAT‐3, in YD‐38 cells. Dasatinib induced activation of the intrinsic caspase pathway, which was inhibited by z‐VAD‐fmk, a pan‐caspase inhibitor. Dasatinib also decreased Mcl‐1 expression and S6 phosphorylation while increased GRP78 expression and eIF‐2α phosphorylation in YD‐38 cells. In addition, to its direct effects on YD‐38 cells, dasatinib also exhibited anti‐angiogenic properties. Dasatinib‐treated YD‐38 or HUVEC showed reduced HIF‐1α expression and stability. Dasatinib alone or conditioned media from dasatinib‐treated YD‐38 cells inhibited HUVEC tube formation on Matrigel without affecting HUVEC viability. Importantly, dasatinib's anti‐growth, anti‐angiogenic and pro‐apoptotic effects were additionally seen in tumorigenic HSC‐3 cells. Together, these results demonstrate that dasatinib has strong anti‐growth, anti‐angiogenic and pro‐apoptotic effects on human oral cancer cells, which are mediated through the regulation of multiple targets, including Src, EGFR, STAT‐3, STAT‐5, PKB, ERK‐1/2, S6, eIF‐2α, GRP78, caspase‐9/3, Mcl‐1 and HIF‐1α.

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 abnobaVISCUMÒ 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 abnobaVISCUMÒ Flaxini at 2 mg/ml for 8 h. Western blot and RT-PCR analyses revealed that abnobaVISCUMÒ 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 abnobaVISCUMÒ Flaxini-treated K562 cells. Moreover, while treatment with abnobaVISCUMÒ 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 abnobaVISCUMÒ Flaxini-induced loss of survival and apoptosis in K562 cells, and z-VAD-fmk also blocked abnobaVISCUMÒ Flaxini-induced Mcl-1 protein down-regulation. Induction of ER stress was also seen in abnobaVISCUMÒ 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 abnobaVISCUMÒ Flaxini-mediated anti-survival and apoptosis inducing effects on K562 cells via activation of caspases, Mcl-1 down-regulation, and triggering ER stress. Disclosures: No relevant conflicts of interest to declare.