• 2019-10
  • 2019-11
  • 2020-03
  • 2020-07
  • 2020-08
  • 2021-03
  • br BBR has been shown to suppresses the transcription


    BBR has been shown to suppresses the transcription of RET growth factor receptor proto-oncogene though stabilization of G-quadruplex structure on the RET promoter region in medullary thyroid carcinoma cells (MTC TT). Due to an abnormal chromosomal rearrangement, the papillary thyroid carcinoma TPC1 cell line lacks the G-quadruplex forming sequence on the RET promoter region. Thus, it is a good negative control model for these studies. BBR was determined to suppress RET expression by more than 90% in MTC
    TT cells containing the RET G-quadruplex structure but not in MTC cells lacking the RET G-quadruplex structure. Down regulation of RET by BBR resulted in activation of apoptosis, increased caspase 3 activity and regulation of certain Nocodazole regulatory proteins (Kumarasamy et al., 2015).
    1.2. BBRs interact with signaling pathways such as NF-kappaB, JAK/STAT, PI3K/PTENAKT/GSK3, RAF/MEK/ERK, and hedgehog
    BBR was shown to inhibit NF-kappaB and the STAT3 pathways in cholangiocarcinoma which induced cell cycle arrest at the G1 phase and suppressed cancer cell growth (Puthdee et al., 2017). Reduced cyclin D1, cyclin E levels and activated levels of STAT3 and ERK1/2 were observed.
    Some of the potential anti-diabetic and anti-cancer effects of BBRs are their abilities to localize to the mitochondria and inhibit the electron transport chain and activate 5′ AMP-activated protein kinase (AMPK) and suppress mTOR activity (Wang et al., 2010). The PI3K/PTEN/Akt/mTORC1 and Raf/MEK/ERK pathways are inhibited when AMPK is activated.
    BBRs can also influence the effect of the MAPK signaling pathways. BBR was determined to inhibit the proliferation of MGC 803 gastric cancer cells in a dose dependent fashion in vitro and in in vivo xenograft studies in mice (Li et al., 2016). The Raf/MEK/ERK pathway was determined to be involved in the effects of BBR on MGC 803 gastric cancer cells. BBR was determined to inhibit interleukin-8 (IL-8) expression. BBR also affected p38MAPK, ERK and c-Jun N-terminal kinase (JNK) expression.
    BBR can also inhibit senescence by altering gero-conversion from the process of cell cycle arrest to the induction of senescence by targeting mTOR/S6 and the generation of ROS (Halicka et al., 2012; Zhao et al., 2013).
    BBR was determined to alter the activity of the hedgehog (Hh) signaling pathway in medulloblastoma cells. Some medullo-blastoma cells may exhibit growth addition 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).
    1.3. BBR effects on drug resistance, epithelial mesenchymal transition, invasion and tumor microenvironment
    The effects of BBR on hypoxia-resistant MCF-7 (MCF/hypoxia) breast cancer cells have been investigated. Hypoxia induced resistance to doxorubicin in MCF-7 cells. Hypoxic growth conditions were demonstrated to induce AMPK activation and doxorubicin-resistance which were dependent upon AMPK-hypoxia inducible factor-1 alpha (HIF-1alpha) dependent P glycoprotein (Pgp) in-activation. High doses of BBR were determined to downregulate AMPK-HIF-1alpha and induce TP53 in this model. These studies demonstrate that BBR can reverse hypoxia induced doxorubicin-resistance through inhibition of AMPK-HIF1alpha and induction of TP53 (Pan et al., 2017).
    BBR can sensitize breast cancer cells to cisplatin and inhibit growth via induction of DNA strand breaks and activation of caspase-3 dependent apoptosis. Cisplatin normally inhibits tumor cell growth by the induction of DNA stand breaks, however, in some cases cisplatin treatment is ineffective due to the development of drug resistance. BBR was determined to increase the effectiveness of cisplatin in inducing DNA strand breaks, caspase-3 and caspase-9 activation and apoptosis (Zhao et al., 2016).