The NAMPT Inhibitor FK866 Increases Metformin Sensitivity in Pancreatic Cancer Cells

Abstract

Pancreatic cancer (pancreatic ductal adenocarcinoma: PDAC) is one of the most aggressive neoplastic diseases. Metformin use has been associated with reduced pancreatic cancer incidence and better survival in diabetics. Metformin has been shown to inhibit PDAC cells growth and survival, both in vitro and in vivo. However, clinical trials using metformin have failed to reduce pancreatic cancer progression in patients, raising important questions about molecular mechanisms that protect tumor cells from the antineoplastic activities of metformin. We confirmed that metformin acts through inhibition of mitochondrial complex I, decreasing the NAD+/NADH ratio, and that NAD+/NADH homeostasis determines metformin sensitivity in several cancer cell lines. Metabolites that can restore the NAD+/NADH ratio caused PDAC cells to be resistant to metformin. In addition, metformin treatment of PDAC cell lines induced a compensatory NAMPT expression, increasing the pool of cellular NAD+. The NAMPT inhibitor FK866 sensitized PDAC cells to the antiproliferative effects of metformin in vitro and decreased the cellular NAD+ pool. Intriguingly, FK866 combined with metformin increased survival in mice bearing KP4 cell line xenografts, but not in mice with PANC-1 cell line xenografts. Transcriptome analysis revealed that the drug combination reactivated genes in the p53 pathway and oxidative stress, providing new insights about the mechanisms leading to cancer cell death.

Inhibitors of NAD+ Production in Cancer Treatment: State of the Art and Perspectives

“…Here, we will just remind the reader that the last two years have witnessed the emergence of new small-molecule chemical NAMPT inhibitors that exhibited very potent anticancer activity against hematological malignancies with IC50 values in the picomolar range [56][57][58]. A synergistic interaction between FK866 and the antidiabetic drug metformin was also recently reported in pancreatic cancer cells [59]. In addition to the conventional small-molecule inhibitors that block NAMPT enzymatic activity, one of the most promising approaches that have recently emerged is to degrade NAMPT by triggering its ubiquitin-mediated proteolysis.…”

Bidirectional relationship between pancreatic cancer and diabetes mellitus: a comprehensive literature review

“…Maintenance of NAD+/NADH homoeostasis affects metformin sensitivity in various cancer cell lines 77 . Furthermore, an in-vitro analysis has shown that the nicotinamide phosphoribosyltransferase (NAMPT) inhibitor FK866 sensitized PDAC cells to metformin’s antiproliferative actions and lowered the cellular NAD+ pool 78 .…”

Metabolic signatures in pancreatic ductal adenocarcinoma: diagnostic and therapeutic implications

“…This synergy hinges on a lowered NAD + /NADH ratio, driving cells to ramp up NAD biosynthesis. [143] This suggests that dual targeting of mitochondria and NAD biosynthesis may result in effective antitumor therapies.…”