Overcoming Cancer Cell Drug Resistance by a Folic Acid Targeted Polymeric Conjugate of Buthionine Sulfoximine.

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.

authors

Cilurzo F,Cristiano MC,Da Pian M,Cianflone E,Quintieri L,Paolino D,Pasut G

doi

10.2174/1871520619666190626114641

subject

Has Abstract

pub_date

2019-01-01 00:00:00

pages

1513-1522

issue

12

eissn

1871-5206

issn

1875-5992

pii

ACAMC-EPUB-99223

journal_volume

19

pub_type

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