Targeting NAD(P)H:quinone oxidoreductase (NQO1) in pancreatic cancer

Abstract

NAD(P)H:quinone oxidoreductase (NQO1) functions as an important part of cellular antioxidant defense by detoxifying quinones, thus preventing the formation of reactive oxygen species (ROS). The aim of our study was to determine if NQO1 is elevated in pancreatic cancer specimens and pancreatic cancer cell lines and if so, would compounds previously demonstrated to redox cycle with NQO1 be effective in killing pancreatic cancer cells. Immunohistochemistry of resected pancreatic specimens demonstrated an increased immunoreactivity for NQO1 in pancreatic cancer and pancreatic intraepithelial neoplasia (PanIN) specimens versus normal human pancreas. Immunocytochemistry and Western immunoblots demonstrated increased immunoreactivity in pancreatic cancer cells when compared to a near normal immortalized human pancreatic ductal epithelial cell line and a colonic epithelial cell line. Streptonigrin, a compound known to cause redox cycling in the presence of NQO1, decreased clonogenic survival and decreased anchorage-independent growth in soft agar. Streptonigrin had little effect on cell lines with absent or reduced levels of NQO1. The effects of streptonigrin were reversed in pancreatic cancer cells pretreated with dicumarol, a known inhibitor of NQO1. NQO1 may be a therapeutic target in pancreatic cancer where survival is measured in months.

Role for NAD(P)H:quinone Oxidoreductase 1 and Manganese-Dependent Superoxide Dismutase in 17-(Allylamino)-17-demethoxygeldanamycin-Induced Heat Shock Protein 90 Inhibition in Pancreatic Cancer Cells

“…NQO1 is an FAD-dependent direct two-electron reductase that can use either NADH or NADPH as reducing cofactor and reduces quinones directly to hydroquinones. Relatively high levels of NQO1 protein and activity have been detected in many human solid tumors, including lung, breast, colon, ovary, and pancreas (Schlager and Powis, 1990;Siegel and Ross, 2000;Lewis et al, 2005). We have demonstrated that NQO1 protein levels in both normal and tumor tissues are influenced by a single-nucleotide polymorphism in the NQO1 gene.…”

NQO1-activated phenothiazinium redox cyclers for the targeted bioreductive induction of cancer cell apoptosis

“…Importantly, constitutive NQO1 overexpression leading to high specific enzymatic activity is associated with various human malignancies including non-small cell lung cancer, pancreas carcinoma, and breast and colon adenocarcinoma, and specific enzymatic activity can differ by up to 20 fold between malignant and unaffected surrounding tissue [42,51]. Recent research suggests that NQO1-overexpression in tumors may serve to accommodate the needs of rapidly metabolizing cells to regenerate NAD + from NADH, a metabolic adaptation of cancer cells that ensures high glycolytic flux independent of NAD + regeneration by mitochondrial respiration that is often compromised in cancer cells [43].…”

Keap1–Nrf2 signalling in pancreatic cancer

“…A prototypical Nrf2 downstream protein, NQO1 (NAD(P)H:quinone oxidoreductase 1), was found to be over-expressed ten-fold compared to normal human pancreatic tissue (Logsdon et al, 2003). Strong immunohistochemical staining for NQO1 has also been demonstrated in premalignant pancreatic dysplastic lesions, known as Pancreatic Intraepithelial Neoplasias (PanINs), suggesting that it is frequently activated early in pancreatic carcinogenesis (Awadallah et al, 2008;Lewis et al, 2005). However, specificity for PDAC may be poor since NQO1 is also over-expressed in non-tumorous pancreatic specimens from smokers, and in pancreatitis tissue Lyn-Cook et al, 2006).…”