• 2019-10
  • 2019-11
  • 2020-03
  • 2020-07
  • 2020-08
  • 2021-03
  • br BBR inhibited the NF B and


    BBR inhibited the NF-κB and the STAT3 pathways in cholangiocarcinoma. This induced cell cycle arrest at the G1 phase which suppressed cancer cell growth (Puthdee et al., 2017). Reduced CYCLIN D1 and CYCLIN E levels and increased levels of activated STAT3 and ERK1/2 were observed.
    BBR also inhibits EGFR signaling and increased the effects of the EGFR inhibitors erlotinib and cetuximab Moniliformin in gastric cancer cells, both in in vitro and in vivo xenograft studies. These results are important as cetuximab plus chemotherapy has been examined in phase 2 clinical trials, however, the combination alone did not provide enough benefit for justification of performing phase 3 clinical trials. BBR was determined to inhibit activation of EGFR in tumors and the combination of BBR and cetuximab was more effective than treatment with either agent by itself. Part of the biochemical mechanism for growth inhibition resulted from decreased phosphor-ylation of STAT3 as well as decreased expression of BCLXL and cyclin D1 (Wang et al., 2016).
    The PI3K/PTEN/AKT/mTORC1/GSK-3 signaling pathway is often regulated by nutraceuticals such as BBR. This pathway plays critical roles in: diabetes, cardiovascular diseases, inflammation, neuropathology, obesity, as well as cancer (McCubrey et al., 2017; Candido et al., 2018; Duda et al., 2018; McCubrey et al., 2018).
    BBR affected AKT expression and its effects on EMT (Kou et al., 2016) by suppressing the migratory and invasive abilities of B16 melanoma cells. BBR altered the pluripotency of EMT-associated factors. BBR treatment suppressed phosphorylation of PI3K and AKT and downregulated retinoic Moniliformin receptor alpha (RARalpha) while increasing RARbeta and RARgamma expression. The PI3K in-hibitor, LY294002, which will suppress AKT activity, had similar effects as BBR on most of the examined biochemical properties, except for RARgamma regulation. Importantly, BBR could reverse EMT in B16 melanoma cells.
    BBRs also has effects on the RAF/MEK/ERK signaling pathway. BBR inhibited the proliferation of MGC 803 gastric cancer cells in vitro and in in vivo xenograft studies in mice (Li et al., 2016). BBR was determined to inhibit interleukin-8 (IL-8) expression. BBR affected p38MAPK, ERK and c-Jun N-terminal kinase (JNK) expression.
    BBR altered the activity of the hedgehog (Hh) signaling pathway in medulloblastoma cells. Some medulloblastoma cells may exhibit growth addiction to the Hh signaling as their proliferation is dependent on activation of this pathway. BBR inhibited the Hh pathway in these cells by suppressing SMO activity. BBR was determined to inhibit Hh-dependent growth both in vitro and in vivo (Wang et al., 2015).
    BBR affected the cisplatin-sensitivity of A2780 ovarian cancer cells. The miR-93/PTEN/AKT signaling pathway was determined to be important in the induction of apoptosis and G0/G1 arrest. BBR treatment resulted in decreased levels of miR-93 cisplatin-resistant cells which reulted in their conversion to cisplatin-sensitive cells. In the absence of miR-93, PTEN tumor suppressor activity re-appeared and inhibited AKT activity and apoptosis occurred. These studies established a regulatory link between miR-93, PTEN and AKT which could be modified by BBR treatment. BBR treatment may also eliminate the effects that miR-93 has on PTEN and relieve cisplatin-resistance in ovarian cancer cells (Chen et al., 2015).
    BBR treatment an also relieve the cisplatin-resistance of gastric cancer cells by upregulation of miR-203 and suppression of the
    S.M. Akula, et al. Advances in Biological Regulation xxx (xxxx) xxxx
    anti-apoptotic protein BCLW. miR-203 can bind mRNAs encoding BCLW and inhibit their expression and induce apoptosis (You et al., 2016). BBR can inhibit drug transporter expression in MCF-7 breast cancer cells. The expression of drug transporters is associated with both drug resistance and cancer stem cells (Kim et al., 2008).