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1.4. BBR can alter gene expression through DNA binding
Some of the more intriguing eﬀects of BBR and modified BBRs may be due to their interactions with nucleic acids. BBR may bind DNA and RNA via the nitrogen Sotrastaurin (AEB071) at the 7-positon in the alkaloid BBR skeleton. Diﬀerent modified BBRs may have distinct interactions with nucleic acids which confer diverse eﬀects on gene expression. Interactions between BBRs and nucleic acids may inhibit telomerases and topoisomerases as well as gene transcript levels by interacting with the TATA-binding protein and TATA-box present in certain gene promoters (Gatto et al., 1996; Qin et al., 2007; Bhowmik et al., 2012a Xiao et al., 2012). Thus, diﬀerent modified BBRs might have diverse eﬀects on gene expression and cellular growth which could be exploited commercially.
In addition, BBRs may induce double strand DNA breaks and cell cycle arrest (Wang et al., 2012). BBRs can also influence gene expression by inhibiting histone deacetylase (HDAC) activity. BBR repressed total HDAC and class I, II and IV HDAC activity by hyperacetylation of histones in A549 lung cancer cells. This resulted in decreases in prostaglandin-endoperoxide synthase 2 (COX2),
Fig. 2. Eﬀects of Berberine on Metabolism, Gene Expression, Induction of miRs, Cellular Proliferation and Metastasis. Berberine has eﬀects on many cellular processes including: metabolism, regulation of gene expression by interaction with DNA and chromatin in the nucleus and signaling pathways. Various miRs are induced by BBR. The mechanisms by which they may aﬀect certain signal transduction and apoptotic pathways which are important in the regulation of cellular growth, malignant transformation, invasion, and drug resistance are depicted briefly in this figure.
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matrix metalloproteinase (MMP2), MMP9 and tumor necrosis factor-alpha (TNF-α) expression and increases in TP53 and p21Cip−1 levels. BBR was determined to regulate apoptotic activity (Kalaiarasi et al., 2016). In this system, BBR could have both direct and indirect eﬀects on DNA by altering chromatin structure and TP53 expression. Thus, there are important interactions between BBR and TP53.
1.5. BBR eﬀects on cisplatin-resistance
Cisplatin normally functions by the induction of DNA strand breaks. BBR can sensitize breast cancer cells to cisplatin and inhibit growth, however, in some cases cisplatin treatment is ineﬀective due to the development of drug-resistance. BBR may increase the eﬀectiveness of cisplatin in inducing DNA strand breaks by augmenting the activation of caspase-3, caspase-9 and apoptosis (Zhao et al., 2016).
In the cisplatin-sensitive OV2008 cell line and in the resistant C13* subline, BBR diﬀerently aﬀected cell growth of sensitive and resistant cells. BBR suppressed the growth of cisplatin-resistant cells more than the sensitive counterparts. This was demostrated to occur by altered expression of genes encoding folate cycle enzymes, such as dihydrofolate reductase (DHFR) and thymidylate syn-thase (TS). BBR also aﬀected polyamine metabolism. This occurred by upregulation of the key catabolic enzyme, spermidine/ spermine N1-acetyltransferase (SSAT). BBR stimulated SSAT induction by the spermine analogue N1, N12 bisethyl¬spermine (BESpm). BESpm downregulated DHFR mRNA more than TS mRNA. BBR treatment reversed the resistance of the cells to cisplatin and BESpm (Marverti et al., 2013).
1.6. BBR eﬀects on signaling pathways implicated in drug resistance
Combining BBR with signal transduction pathway inhibitors can inhibit the drug resistance of certain cancers. BBR can interact with the epidermal growth factor receptor (EGFR)/human epidermal growth factor receptor (HER2) inhibitor lapatinib and suppress the resistance of HER2+ breast cancer (Zhang et al., 2016). In lapatinib-resistant cells, lapatinib induces c-MYC/pro-NRF2 and GSK-3beta signaling pathways. This results in stabilization of NRF2. In contrast, BBR treatment prevents some aspects of the growth promoting eﬀects of lapatinib such as the induction of c-MYC expression. The combination of BBR and lapatinib decreased c-MYC expression, lapatinib-resistance and cell growth.