, 2000, Valabrega et al., 2007 and Sun et al., 2011). Berberine (BBR), which is a natural alkaloid, was reported to inhibit cell proliferation and induce apoptosis by suppressing HER2 expression and the HER2-mediated PI3K/Akt signaling pathway in HER2-overexpressing breast cancer cells, such as SK-BR-3, BT474, and HER2-overexpressing MCF-7 (MCF-7/HER2) cells ( Kuo et al., 2011). this website The extent of the reduction of phospho-HER2/phospho-Akt induced by BBR treatment (25 or 50 μM for 24 or 48 h) was stronger

in SK-BR-3 cells than that in BT474 and MCF-7/HER2 cell lines. Unlike BBR, CHO10 induced a significant decrease in the protein levels of phospho-HER2, phospho-MAPK and phospho-Akt with a smaller amount (10 μM treatment for 16 h) than BBR in SK-BR-3 cells (25 or 50 μM for 24 or 48 h). Luteolin, which is a naturally occurring flavonoid, was reported to effectively inhibit cell proliferation and induce apoptosis in HER2-overexpressing cancer cells, including AU565, MDA-MB-453 and SKOV3.ip1 ( Chiang et al., 2007). Luteolin considerably reduced the level of the HER protein with a 20 or 40 μM treatment for 24 h and preferentially inhibited the proliferation of HER2-overexpressing cancer cells; a 20 μM luteolin treatment blocked >60% of the growth in AU565, MDA-MB-453 and SKOV3.ip1 cells, while it was

much less effective in MCF-7 and HBL-100 cells that expressed basal levels of HER2 under the same conditions. The mechanism

of the Rolziracetam luteolin-mediated HER2 down-regulation VRT752271 chemical structure is different from that of CHO10; luteolin promotes HER2 degradation through dissociating HER2 from Hsp90 without significantly affecting the level of Hsp90. Although the mechanism of HER2 depletion is different from each other, both CHO10 and luteolin are able to inhibit preferentially the proliferation of HER2-overexpressing cancer cells ( Fig. 2A) ( Chiang et al., 2007). The ESX–Sur2 interaction inhibitory activity of CHO10 led to the down-regulation of HER2 and caused apoptosis in a dose- and time-dependent manner, as demonstrated by the increase in sub G1 population (Fig. 2C and D) and cleaved PARP level ( Fig. 2E) without caspase-3 activation (Fig. 3A and B). The mechanism underlying caspase-independent cell death is very complex ( Donovan and Cotter, 2004). PARP can directly induce apoptosis regardless of caspase-3 activation by stimulating the release of apoptosis initiating factor (AIF), which translocates into the nucleus ( Yu et al., 2006). BBR was reported to induce apoptosis by activating the mitochondria/caspase pathway in HER2-overexpressing breast cancer SK-BR-3 cells ( Kuo et al., 2011) and was also reported to lead to colon tumor cell death through PARP activation-dependent AIF activation without stimulating caspase activation. The BBR-induced colon cell death was not affected by co-treatment with a caspase inhibitor ( Wang et al., 2012).