br Combining BBR with signal transduction inhibitors chemoth
1.4. Combining BBR with signal transduction inhibitors, chemotherapeutic drugs and other therapeutic agents
The drug resistance of various cancer Amiloride HCL can be reversed or reduced by combining BBR with certain signal transduction pathway inhibitors. BBR seems to interact well with EGFR inhibitors to reduce the resistance of certain cancers to various drug and signal transduction inhibitors (Zhang et al., 2016). Co-addition of the dual EGFR/HER2 inhibitor lapatinib and BBR inhibited the lapatinib-resistance of HER2+ breast cancer. This co-addition resulted in the elevated ROS levels. In lapatinib-resistant cells, lapatinib induces c-MYC/pro-NRF2 and GSK-3beta signaling pathways and stabilization of NRF2 and low levels of ROS. In contrast, BBR treatment prevents some aspects of the growth promoting eﬀects of lapatinib as c-MYC expression was decreased and the levels of ROS were increased. Consequently, the combination of BBR and lapatinib resulted in decreased c-MYC expression, lapatinib-resistance and cell
BBR also inhibits EGFR signaling and increased the eﬀects of the EGFR inhibitors erlotinib and cetuximab 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 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 phosphorylation of STAT3 and decreased expression of BCL-XL and cyclin D1 (Wang et al., 2016).
We have recently reviewed various modified BBR compounds that have been developed (McCubrey et al., 2017b). In this current manuscript, we will include some novel advances to the field. Various medicinal chemical approaches have been made to design more active BBRs and other nutraceuticals (Bhowmik and Kumar, 2016). NO-donating protoberberines have been developed which display more potent activity against certain tumor cells such as HepG2 hepatocellular carcinoma cells (Chen et al., 2017). These compounds released NO and the anti-tumor eﬀects of certain compounds could be inhibited by an NO scavenger. Compound 15a developed by this group exhibited a broad anti-tumor eﬃcacy and was selective against hepatocellular tumor cells as opposed to normal liver LO-2 cells. Compound 15a was determined to block HepG2 cells in the G2 phase of the cell cycle and induce apoptosis.
The 13-phenylalkyl and 13-diphenylalkyl BBR derivative NAX compounds were determined to result in telomeric DNA G-quadruplexes. The NAX042 and NAX053 compounds were examined in terms of telomeric G-quadruplexes in this system (Ferraroni et al., 2016). NAX042 and NAX053 were the best compounds in terms of simulating the interaction with human telomeric DNA G4 structures.
1.6. Pancreatic cancer
Pancreatic cancer is a devastating disease which is frequently diagnosed late with few eﬀective therapeutic options available. We have recently summarized the genetic and environmental risk factors as well as the therapeutic approaches that are important with regards to pancreatic cancer (Fitzgerald and McCubrey, 2014; Fitzgerald et al., 2015; Candido et al., 2018; Abrams et al., 2018). Pancreatic cancer will soon be the second most common cancer in terms of cancer death. Most pancreatic cancers are pancreatic ductal adenocarcinoma (PDAC).
2. Materials and methods
2.1. Cell lines and tissue culture
Cells were cultured in Dulbecco's modified Eagles medium, (DMEM), (Invitrogen, Carlsbad, CA), antibiotics containing L-gluta-mine medium containing 5% fetal bovine serum (FBS) purchased from Atlanta Biologicals, (Atlanta, GA, USA) as described in (Abrams et al., 2018). NAX compounds were generously provided by our collaborator and co-author, Dr. Paolo Lombardi (Naxo-spharma, Milan, Italy). BBR was purchased from Sigma-Aldrich (Saint Louis, MO, USA).