br Keywords br Berberine br PDAC br Signal transduction inhi
Signal transduction inhibitors Chemotherapeutic drugs
Berberine (BBR) is a common nutraceutical consumed by millions worldwide. BBR has many diﬀerent eﬀects on human health, e.g., diabetes, diarrhea, inflammation and now more recently it has been proposed to have potent anti-cancer eﬀects. BBR has been shown to suppress the growth of cancer cells more than normal cells. BBR has been proposed to exert its growth-inhibitory eﬀects by many diﬀerent biochemical mechanisms including: suppression of Dynasore progres-sion, induction of reactive oxygen species, induction of apoptosis and autophagy and interactions with DNA potentially leading to DNA damage, and altered gene expression. Pancreatic cancer is a leading cancer worldwide associated with a poor prognosis. As our population ages, pancreatic cancer has an increasing incidence and will likely become the second leading cause of death from cancer. There are few truly-eﬀective therapeutic options for pancreatic cancer. Surgery and certain chemotherapeutic drugs are used to treat pancreatic cancer patients. Novel approaches to treat pancreatic cancer patients are direly needed as they usually survive for less than a year after being diagnosed. In the following manuscript, we discuss the abilities of BBR and certain che-mically-modified BBRs (NAX compounds) to suppress growth of pancreatic cancer cells.
∗ Corresponding author. ∗∗ Corresponding author. E-mail address: [email protected] (J.A. McCubrey).
Berberine (BBR) is a commonly-consumed nutraceutical which has been investigated for prevention/treatment of various diseases and ailments for centuries (McCubrey et al., 2017a, 2017b, 2017c; McCubrey et al., 2018). Berberine is contained in fruits and berries such as: Berberis aetnensis C. Presl., Berberis aristata, Berberis vulgaris, Coptis chinensis, Coptis japonica, Coptis rhizome, Hydrastis ca-nadensis, Phellondendron amurense and Tinosora cordifolia. BBR is an isoquinoline quaternary alkaloid (a 5,6-dihydrodibenzo[a,g] quinolizinium derivative). The health promoting eﬀects of BBR have been known for centuries. BBR is often employed in traditional Chinese and Indian medicine. BBR is consumed for alleviation of various conditions/diseases such as: abdominal pain, coronary artery disease, diabetes, diarrhea, fatty liver disease, gastroenteritis, hyperlipidemia, hypertension, metabolic syndrome, neurode-generation, obesity, polycystic ovary syndrome. BBR is sold over the counter in many countries as a nutraceutical, it is often con-tained in the section of the store that sells products for sugar control. Importantly, in recent years the clinical interest in the health promoting eﬀects of BBR has strikingly increased as shown by only 9 clinical trials in 2011 and more than 50 today, 4 of which are in the oncological area.
In this regard, a new aspect of the therapeutic potential of BBR may be in the treatment of certain cancers (Guamán Ortiz et al., 2014a,b). BBRs can also influence the expression of various processes that are involved in growth control such as: apoptosis, au-tophagy, metastasis and proliferation and specifically genes including: BCL2, BCLXL, PARP1 (Poly ADP-Ribose Polymerase 1), BECN1 (Beclin-1), TP53, cyclin dependent kinase inhibitor 1A (CDKN1A = p21Cip1), and MMP9 (Matrix Metallopeptidase 9) (Cordell et al., 2001; Tillhon et al., 2012). BBRs have eﬀects on the expression of genes important in apoptosis. BBR suppressed BCL2A1 (BCL2 Related Protein A1), MCL1 (Induced myeloid leukemia cell diﬀerentiation protein) and BCL2L2 (BCL2 Like 2 = BCL-w) while ac-tivating BAX (BCL2 Associated X) and BAK (BCL2 Antagonist/Killer 1) in melanoma cells (Xu et al., 2017).
1.1. BBR interactions with nucleic acids
Some of the eﬀects of BBR may be due to its interactions with nucleic acids. Specifically, BBR may form complexes with DNA and RNA via the nitrogen atom at the 7-positon in the alkaloid BBR skeleton. This interaction between BBR and nucleic acids may inhibit telomerases and topoisomerases (Gatto et al., 1996; Kim et al., 1998; Qin et al., 2007; Bhowmik et al., 2012a). BBR may aﬀect gene transcription by interacting with the TATA-binding protein and the TATA-box present in certain promoter regions which are involved in growth control (e.g., BCL2) (Wang et al., 2011; Xiao et al., 2012). In addition, BBR may induce double strand DNA breaks and cell cycle arrest (Wang et al., 2012). BBRs can influence chromatin remodeling 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. In these studies, BBR downregulated the expression of COX2 (Prostaglandin-endoperoxide synthase 2), MMP2 and MMP9 and TNF-alpha and upre-gulated p21Cip−1 and TP53 expression. BBR was determined to regulate BCL2/BAX family expression and induced the caspase cascade and apoptosis. Thus, BBR may also have eﬀects by HDAC inhibition which results in epigenetic reprogramming (Kalaiarasi et al., 2016).