Abstract:
BACKGROUND:Glutathione (GSH), which is the predominant low molecular weight intracellular thiol in mammals, has multiple functions, such as those of protecting against oxidative stress and detoxifying endogenous and exogenous electrophiles. High GSH levels, which have been observed in various types of tumors, have been thought to contribute to the resistance of neoplastic cells to apoptotic stimuli triggered by pro-oxidant therapy. Although L-(S,R)-Buthionine Sulfoximine (BSO), a selective irreversible inhibitor of glutamate cysteine ligase, depletes GSH in vitro and in in vivo and sensitizes tumor cells to radiation and some cancer chemotherapeutics, its toxicity and short in vivo half-life have limited its application to combination anticancer therapies. OBJECTIVE:To demonstrate that a folate-targeted PEGylated BSO conjugate can sensitize cancer cells to a Reactive Oxygen Species (ROS)-generating anticancer agent by depleting GSH. METHODS:A novel folate-targeted PEGylated-BSO conjugate was synthesized and tested in combination with gemcitabine in human cell lines that over-express (HeLa) or do not express (A549) the folate receptor. RESULTS:The prepared folate-PEG-GFLG-BSO conjugate proved to be efficacious in reducing GSH levels and, when used in combination with the pro-oxidant drug gemcitabine, it enhanced drug activity in the cell line overexpressing the folate receptor. CONCLUSION:The folate-PEG-GFLG-BSO conjugate studied was found to be effective in sensitizing folatereceptor positive cancer cells to the ROS-generating drug gemcitabine.
journal_name
Anticancer Agents Med Chemjournal_title
Anti-cancer agents in medicinal chemistryauthors
Cilurzo F,Cristiano MC,Da Pian M,Cianflone E,Quintieri L,Paolino D,Pasut Gdoi
10.2174/1871520619666190626114641subject
Has Abstractpub_date
2019-01-01 00:00:00pages
1513-1522issue
12eissn
1871-5206issn
1875-5992pii
ACAMC-EPUB-99223journal_volume
19pub_type
杂志文章abstract:BACKGROUND:Bendamustine, an N-mustard-benzoimidazole hybrid conjugate, was recently approved for the treatment of chronic lymphocytic leukemia. However, the short half-life of bendamustine may limit its clinical applications. OBJECTIVE:The purpose of this study is to design and synthesize compounds with a more favorab...
journal_title:Anti-cancer agents in medicinal chemistry
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doi:10.2174/1871520617666170522120200
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abstract::Hepatocellular carcinoma (HCC) is a cancer with extremely poor prognosis. This review discusses the pathological characteristics of multi-step hepatocarcinogenesis, tumor growth, invasion and metastasis, the expression of matrix metalloproteinases (MMPs) and their inhibitors via signal transduction in relation to dedi...
journal_title:Anti-cancer agents in medicinal chemistry
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journal_title:Anti-cancer agents in medicinal chemistry
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journal_title:Anti-cancer agents in medicinal chemistry
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journal_title:Anti-cancer agents in medicinal chemistry
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journal_title:Anti-cancer agents in medicinal chemistry
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journal_title:Anti-cancer agents in medicinal chemistry
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journal_title:Anti-cancer agents in medicinal chemistry
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journal_title:Anti-cancer agents in medicinal chemistry
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journal_title:Anti-cancer agents in medicinal chemistry
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journal_title:Anti-cancer agents in medicinal chemistry
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doi:
更新日期:2013-03-01 00:00:00
abstract:INTRODUCTION:Esophageal cancer remains an aggressive disease with poor survival rates. FAK and IGF-1R are two important tyrosine kinases important for cell survival signaling and found to be upregulated in esophageal cancer. Our hypothesis is that a novel small molecule compound that disrupts FAK and IGF-1R protein-pro...
journal_title:Anti-cancer agents in medicinal chemistry
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journal_title:Anti-cancer agents in medicinal chemistry
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更新日期:2017-01-01 00:00:00
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journal_title:Anti-cancer agents in medicinal chemistry
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journal_title:Anti-cancer agents in medicinal chemistry
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journal_title:Anti-cancer agents in medicinal chemistry
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journal_title:Anti-cancer agents in medicinal chemistry
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journal_title:Anti-cancer agents in medicinal chemistry
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journal_title:Anti-cancer agents in medicinal chemistry
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journal_title:Anti-cancer agents in medicinal chemistry
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