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

被引：29

作者：

Beg, Muhammad Shaalan ^{[1
,2
]}

Huang, Xiumei ^{[2
,3
,4
]}

Silvers, Molly A. ^{[2
]}

Gerber, David E. ^{[1
,2
]}

Bolluyt, Joyce ^{[2
]}

Sarode, Venetia ^{[2
,5
]}

Fattah, Farjana ^{[2
]}

Deberardinis, Ralph J. ^{[3
,4
,6
]}

Merritt, Matthew E. ^{[7
]}

Xie, Xian-Jin ^{[2
]}

Leff, Richard ^{[8
]}

Laheru, Daniel ^{[9
]}

Boothman, David A. ^{[2
,3
,4
]}

机构：

[1] Univ Texas Southwestern Med Ctr Dallas, Dept Internal Med, Div Hematol & Oncol, 5323 Harry Hines Blvd, Dallas, TX 75390 USA

[2] Univ Texas Southwestern Med Ctr Dallas, Harold Simmons Comprehens Canc Ctr, Dallas, TX 75390 USA

[3] Univ Texas Southwestern Med Ctr Dallas, Dept Pharmacol, Dallas, TX USA

[4] Univ Texas Southwestern Med Ctr Dallas, Dept Radiat Oncol, Dallas, TX 75390 USA

[5] Univ Texas Southwestern Med Ctr Dallas, Dept Pathol, Dallas, TX USA

[6] Univ Texas Southwestern Med Ctr Dallas, Childrens Med Ctr, Res Inst, Dallas, TX 75390 USA

[7] Univ Florida, Dept Biochem & Mol Biol, Gainesville, FL 32610 USA

[8] Texas Tech Univ, Hlth Sci Ctr, Clin Pharmacol & Expt Therapeut Ctr, Sch Pharm, Dallas, TX USA

[9] Johns Hopkins Univ, Sidney Kimmel Canc Ctr, Baltimore, MD USA

来源：

JOURNAL OF SURGICAL ONCOLOGY | 2017年 / 116卷 / 01期

关键词：

beta-lapachone; cancer metabolism; experimental therapeutics; hyperpolarization; pancreatic cancer; CHIMERIC-ANTIGEN-RECEPTOR; STEM-CELL ANTIGEN; CAR-T-CELLS; TUMOR-ASSOCIATED MACROPHAGES; MESOTHELIN-RELATED PROTEIN; ANTITUMOR-ACTIVITY; B-CELL; CARCINOEMBRYONIC ANTIGEN; PHYSICAL BARRIERS; MOUSE MODEL;

D O I：

10.1002/jso.24624

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

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 (H2O2) 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.

引用

页码：83 / 88

页数：6

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