Using a novel NQO1 bioactivatable drug, beta-lapachone (ARQ761), to enhance chemotherapeutic effects by metabolic modulation in pancreatic cancer.

ABSTRACT: Novel, tumor-selective therapies are needed to increase the survival rate of pancreatic cancer patients. K-Ras-mutant-driven NAD(P)H:quinone oxidoreductase 1 (NQO1) is over-expressed in pancreatic tumor versus associated normal tissue, while catalase expression is lowered compared to levels in associated normal pancreas tissue. ARQ761 undergoes a robust, futile redox cycle in NQO1+ cancer cells, producing massive hydrogen peroxide (H₂ O₂ ) levels; normal tissues are spared by low NQO1 and high catalase expression. DNA damage created by ARQ761 in pancreatic cancer cells "hyperactivates" PARP1, causing metabolic catastrophe and NAD ± keresis cell death. NQO1: catalase levels (high in tumor, low in normal tissue) are an attractive therapeutic window to treat pancreatic c

SUBMITTER: Beg MS 

PROVIDER: S-EPMC5509448 | biostudies-literature | 2017 Jul

REPOSITORIES: biostudies-literature