Pharmacologic ascorbate synergizes with gemcitabine in preclinical models of pancreatic cancer

被引:132
作者
Espey, Michael Graham [3 ]
Chen, Ping [1 ,2 ]
Chalmers, Brian [1 ]
Drisko, Jeanne [1 ]
Sun, Andrew Y. [3 ]
Levine, Mark [3 ]
Chen, Qi [1 ]
机构
[1] Univ Kansas, Med Ctr, Dept Pharmacol Toxicol & Therapeut, Program Integrat Med, Kansas City, KS 66160 USA
[2] Xi An Jiao Tong Univ, Sch Med, Dept Genet & Mol Biol, Xian 710061, Peoples R China
[3] NIDDKD, Mol & Clin Nutr Sect, NIH, Bethesda, MD 20892 USA
关键词
Pancreatic cancer; Drug synergy; Ascorbate; Vitamin C; Gemcitabine; Free radicals; DOSE VITAMIN-C; OXIDATIVE STRESS; HYDROGEN-PEROXIDE; DNA-DAMAGE; MESENCHYMAL TRANSITION; INDUCED CYTOTOXICITY; CONTROLLED-TRIAL; DRUG-RESISTANCE; CELLS; ACID;
D O I
10.1016/j.freeradbiomed.2011.03.007
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Conventional treatment approaches have had little impact on the course of pancreatic cancer, which has the highest fatality rate among cancers. Gemcitabine, the primary therapeutic agent for pancreatic carcinoma, produces minimal survival benefit as a single agent. Therefore, numerous efforts have focused on gemcitabine combination treatments. Using a ratio design, this study established that combining pharmacologically achievable concentrations of ascorbate with gemcitabine resulted in a synergistic cytotoxic response in eight pancreatic tumor cell lines. Sensitization was evident regardless of inherent gemcitabine resistance and epithelial-mesenchymal phenotype. Our analysis suggested that the promiscuous oxidative actions of H2O2 derived from pharmacologic ascorbate can culminate in synergism independent of the cancer cell's underlying phenotype and resistance to gemcitabine monotherapy. Gemcitabine-ascorbate combinations administered to mice bearing pancreatic tumor xenografts consistently enhanced inhibition of growth compared to gemcitabine alone, produced 50% growth inhibition in a tumor type not responsive to gemcitabine, and demonstrated a gemcitabine dose-sparing effect. These data support the testing of pharmacologic ascorbate in adjunctive treatments for cancers prone to high failure rates with conventional therapeutic regimens, such as pancreatic cancer. (C) 2011 Elsevier Inc. All rights reserved.
引用
收藏
页码:1610 / 1619
页数:10
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