Metformin influences drug sensitivity in pancreatic cancer cells

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is an aggressive, highly metastatic malignancy and accounts for 85% of pancreatic cancers. PDAC patients have poor prognosis with a five-year survival of only 5-10% after diagnosis and treatment. Pancreatic cancer has been associated with type II diabetes as the frequency of recently diagnosed diabetics that develop pancreatic cancer within a 10-year period of initial diagnosis of diabetes in increased in comparison to non-diabetic patients. Metformin is a very frequently prescribed drug used to treat type II diabetes. Metformin acts in part by stimulating AMP-kinase (AMPK) and results in the suppression of mTORC1 activity and the induction of autophagy. In the following studies, we have examined the effects of metformin in the presence of various chemotherapeutic drugs, signal transduction inhibitors and natural products on the growth of three different PDAC lines. Metformin, by itself, was not effective at suppressing growth of the pancreatic cancer cell lines at concentration less than 1000 nM, however, in certain PDAC lines, a suboptimal dose of metformin (250 nM) potentiated the effects of various chemotherapeutic drugs used to treat pancreatic cancer (e.g., gemcitabine, cisplatin, 5-fluorouracil) and other cancer types (e.g., doxorubicin, docetaxel). Furthermore, metformin could increase anti-proliferative effects of mTORC1 and PI3K/mTOR inhibitors as well as natural products such as berberine and the anti-malarial drug chloroquine in certain PDAC lines. Thus, metformin can enhance the effects of certain drugs and signal transduction inhibitors which are used to treat pancreatic and various other cancers.

Abilities of berberine and chemically modified berberines to interact with metformin and inhibit proliferation of pancreatic cancer cells

“…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).…”

“…Metformin (N,N-dimethylimidodicarbonimidic diamide) is a type II diabetes drug which also has effects on cancer (Lonardo et al, 2013;Candido et al, 2018). Metformin mainly blocks hepatic gluconeogenesis.…”

Effects of the MDM-2 inhibitor Nutlin-3a on PDAC cells containing and lacking WT-TP53 on sensitivity to chemotherapy, signal transduction inhibitors and nutraceuticals

“…The development of PDAC is complex and includes both environmental, as well as, genetic risk factors (Klein, 2012). We have recently summarized the risk and genetic factors associated with development of pancreatic cancer (Abrams et al, 2018(Abrams et al, , 2019Candido et al, 2018). Some of the risk factors for PDAC development in the USA are race and gender based, as well as, diabetes and obesity.…”

“…Cells were cultured in medium containing 5% fetal bovine serum (FBS) (Atlanta Biologicals, Atlanta, GA, USA) as described in (Abrams et al, 2017(Abrams et al, , 2018(Abrams et al, , 2019Steelman et al, 2017;Candido et al, 2018). Tissue culture medium (Dulbecco's modified Eagles medium, DMEM), antibiotics containing L-glutamine and trypsin were obtained from Invitrogen (Carlsbad, CA, USA).…”

“…(For interpretation of the references to colour in this figure legend, the reader is referred to the Web version of this article.) Candido et al Advances in Biological Regulation xxx (xxxx) xxx-xxx and statistical analyses were determined as described (Abrams et al, 2018(Abrams et al, , 2019Candido et al, 2018). Statistical analysis is described in materials and methods and results section.…”