Premium
Using a novel NQO1 bioactivatable drug, beta‐lapachone (ARQ761), to enhance chemotherapeutic effects by metabolic modulation in pancreatic cancer
Author(s) -
Beg Muhammad Shaalan,
Huang Xiumei,
Silvers Molly A.,
Gerber David E.,
Bolluyt Joyce,
Sarode Venetia,
Fattah Farjana,
Deberardinis Ralph J.,
Merritt Matthew E.,
Xie XianJin,
Leff Richard,
Laheru Daniel,
Boothman David A.
Publication year - 2017
Publication title -
journal of surgical oncology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.201
H-Index - 111
eISSN - 1096-9098
pISSN - 0022-4790
DOI - 10.1002/jso.24624
Subject(s) - pancreatic cancer , catalase , medicine , nad+ kinase , cancer research , parp1 , gemcitabine , cancer , pancreas , chemotherapy , enzyme , biology , oxidative stress , biochemistry , poly adp ribose polymerase , polymerase
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 (H 2 O 2 ) 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 cancer. Based on a growing body of literature, we are leading a clinical trial to evaluate the combination of ARQ761 and chemotherapy in patients with pancreatic cancer.