br The e ects of BBR and
The eﬀects of BBR and cisplatin were also examined in ovarian cancer cells. In A2780 cells, it was demonstrated that BBR induced sensitivity to cisplatin via activation of the miR-93/PTEN/AKT signaling pathway and the induction of apoptosis and G0/G1 arrest. The levels of miR-93 were determined to be higher in cisplatin-resistant than cisplatin-sensitive cells. BBR inhibited the expression of micro RNA-93 (miR-93) which resulted in loss of its inhibitory eﬀects on the PTEN tumor suppressor and potentially also inhibited AKT activity as PTEN activity would be stimulated. These studies document a regulatory link between miR-93, PTEN and AKT which was suppressed by BBR treatment. Disruption of this link can relieve cisplatin-resistance in ovarian cancer Pimozide (Chen et al., 2015). In the cisplatin-sensitive OV2008 cell line and in the resistant C13* subline, BBR diﬀerently aﬀected cell growth of sensitive and resistant cells and also in the polyamine analogue cross-resistant human ovarian cancer cells. BBR was shown to suppresses the growth of cisplatin-resistant cells more than the sensitive counterparts, by interfering with the expression of folate cycle enzymes, dihydrofolate reductase (DHFR) and thymidylate synthase (TS). BBR inhibited cellular growth by aﬀecting polyamine metabolism, in particular through the upregulation of the key catabolic enzyme, spermidine/spermine N1-acetyltransferase (SSAT). BBR was also shown to stimulate SSAT induction by the spermine analogue N1, N12 bisethylspermine (BESpm), which alone was also able to downregulate DHFR mRNA more than TS mRNA. The sensitivity of resistant cells to cisplatin or to BESpm was reverted to the levels of sensitive cells by the co-treatment with berberine, confirming the intimate inter-relationships between folate cycle and polyamine pathways and suggesting that the isoquinoline plant alkaloid BBR could be a useful adjuvant therapeutic agent in the treatment of ovarian carcinoma (Marverti et al., 2013).
BBR was determined to reduce cisplatin-resistance in human gastric cancer cells by upregulation of miR-203 and suppression of the anti-apoptotic protein Bcl-w. miR-203 can bind Bcl-w and suppress its expression and induce apoptosis (You et al., 2016).
BBR can inhibit drug transporter expression in MCF-7 cells that is associated with both drug resistance and some of the properties of cancer stem cells (Kim et al., 2008).
BBR can influence the activity of AKT and its role in epithelial-mesenchymal transition (EMT) (Kou et al., 2016). BBR inhibited the migratory and invasive abilities of B16 melanoma cells. This was determined to occur by BBR altering the pluripotency of EMT associated factors. BBR decreased the expression of phosphorylated PI3K and AKT and downregulated retinoic acid receptor alpha (RARalpha). In contrast, BBR increased the expression of RARbeta and RARgamma. The PI3K inhibitor LY294002 was determined to have similar eﬀects as BBR, with the exception of RARgamma regulation. Interestingly, these studies demonstrated that BBR could reverse EMT in B16 melanoma cells.
BBR inhibited vasodilator-stimulated phosphoprotein (ASP) expression in breast cancer cells. VASP normally stimulates actin filament elongation and cell migration. BBR was demonstrated to bind VASP, alter its structure and actin elongation and poly-merization and inhibit motility and proliferation of normally highly motile MDA-MB-231 breast cancer cells both in vitro and in vivo mouse xenograft studies (Su et al., 2016).
BBR and other nutraceuticals will aﬀect the tumor microenvironment (Casey et al., 2015). BBR can inhibit vascular endothelial growth factor (VEGF) expression in Hep-G2 cells and inhibit their angiogenic properties (Jie et al., 2011).