Combination therapy with BPTES nanoparticles and metformin targets the metabolic heterogeneity of pancreatic cancer

Elgogary Amira; Xu Qingguo; Poore BradAlt JesseZimmermann Sarah C.Zhao LiangFu JieChen BaiweiXia ShiyuLiu YanfeiNeisser MarcNguyen ChristopherLee RamonPark Joshua K.Reyes JuvenalHartung ThomasRojas CamiloRais RanaTsukamoto TakashiSemenza Gregg L.Hanes JustinSlusher Barbara S.Le Anne

首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America. >Combination therapy with BPTES nanoparticles and metformin targets the metabolic heterogeneity of pancreatic cancer

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Combination therapy with BPTES nanoparticles and metformin targets the metabolic heterogeneity of pancreatic cancer

机译：Combination therapy with BPTES nanoparticles and metformin targets the metabolic heterogeneity of pancreatic cancer

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Targeting glutamine metabolism via pharmacological inhibition of glutaminase has been translated into clinical trials as a novel cancer therapy, but available drugs lack optimal safety and efficacy. In this study, we used a proprietary emulsification process to encapsulate bis-2-(5-phenylacetamido-1,2,4-thiadiazol-2-yl) ethyl sulfide (BPTES), a selective but relatively insoluble glutaminase inhibitor, in nanoparticles. BPTES nanoparticles demonstrated improved pharmacokinetics and efficacy compared with unencapsulated BPTES. In addition, BPTES nanoparticles had no effect on the plasma levels of liver enzymes in contrast to CB-839, a glutaminase inhibitor that is currently in clinical trials. In a mouse model using orthotopic transplantation of patient-derived pancreatic tumor tissue, BPTES nanoparticle monotherapy led to modest antitumor effects. Using the HypoxCR reporter in vivo, we found that glutaminase inhibition reduced tumor growth by specifically targeting proliferating cancer cells but did not affect hypoxic, noncycling cells. Metabolomics analyses revealed that surviving tumor cells following glutaminase inhibition were reliant on glycolysis and glycogen synthesis. Based on these findings, metformin was selected for combination therapy with BPTES nanoparticles, which resulted in significantly greater pancreatic tumor reduction than either treatment alone. Thus, targeting of multiple metabolic pathways, including effective inhibition of glutaminase by nanoparticle drug delivery, holds promise as a novel therapy for pancreatic cancer.

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《Proceedings of the National Academy of Sciences of the United States of America.》 |2016年第36期|E5328-E5336|共9页
作者
Elgogary Amira; Xu Qingguo; Poore BradAlt JesseZimmermann Sarah C.Zhao LiangFu JieChen BaiweiXia ShiyuLiu YanfeiNeisser MarcNguyen ChristopherLee RamonPark Joshua K.Reyes JuvenalHartung ThomasRojas CamiloRais RanaTsukamoto TakashiSemenza Gregg L.Hanes JustinSlusher Barbara S.Le Anne;
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作者单位

Johns Hopkins Univ, Sch Med, Dept Pathol, Baltimore, MD 21205 USA;

Johns Hopkins Univ, Sch Med, Johns Hopkins Drug Discovery, Baltimore, MD 21205 USA;

Johns Hopkins Univ, Sch Med, Dept Radiat Oncol, Baltimore, MD 21205 USAUniv Konstanz, Ctr Alternat Anim Testing, D-78464 Constance, GermanyJohns Hopkins Univ, Sch Med, Wilmer Eye Inst Ctr Nanomed, Baltimore, MD 21205 USAJohns Hopkins Univ, Sch Med, Dept Ophthalmol, Baltimore, MD 21205 USAJohns Hopkins Bloomberg Sch Publ Hlth, Dept Environm Hlth Sci, Baltimore, MD 21205 USA;

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收录信息美国《科学引文索引》(SCI);美国《生物学医学文摘》(MEDLINE);美国《化学文摘》(CA);
原文格式 PDF
正文语种英语
中图分类自然科学总论;
关键词
pancreatic ductal adenocarcinoma; glutaminolysis; glucose metabolism; KRAS mutation; intratumoral hypoxia;

Combination therapy with BPTES nanoparticles and metformin targets the metabolic heterogeneity of pancreatic cancer

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