Doxorubicin‐induced oxygen free radical formation in sensitive and doxorubicin‐resistant variants of rat glioblastoma cell lines

Abstract

We have studied the formation of hydroxyl radical (OH•) induced by doxorubicin in a series of doxorubicin‐ or vincristine‐selected variants of C6 rat glioblastoma cells in culture by electron‐spin resonance spectroscopy using 5,5′‐dimethyl‐1‐pyrroline‐1‐oxide as a spin trap. Wild‐type cells, sensitive to doxorubicin, exhibited in the presence of this drug a concentration‐dependent OH• formation which could be inhibited by preincubation with superoxide dismutase, catalase or an antibody against cytochrome P450‐reductase. In highly doxorubicin‐resistant cells, OH• formation was reduced to about 20% of the level obtained in sensitive cells. In cells presenting a very low level of resistance to doxorubicin or in cells selected with vincristine, both presenting a pure multidrug‐resistant phenotype, OH• formation was identical to that obtained in sensitive cells. In cells of intermediate resistance or in revertant cells, intermediate levels of OH• formation were obtained. Protection against OH• formation and action can be identified at the levels of superoxide dismutase and glutathione peroxidase activities, which are both enhanced in the resistant cells.

A proteomic analysis of an in vitro knock-out of miR-200c

“…suggest ALDH7A1 may play an important role in the defense of the cell against oxidative stress and its cytotoxicity 63 . As the cytotoxic effect of doxorubicin and similar drugs is in parts accounted to reactive oxygen species (ROS) and oxidative stress 64 , 65 , the loss of miR-200c may cause the increase of ALHD7A1, leading to an increase in resistance to these therapeutics.…”

Cathepsin B-Cleavable Cyclopeptidic Chemotherapeutic Prodrugs

“…DOX ( Figure 1 ) is an anthracycline antibiotic used in the treatment of a large number of pathologies including acute myeloblastic leukemia, acute lymphocytic leukemia, bladder cancer, breast cancer, gastric cancer, head and neck cancer, squamous cell carcinoma, Hodgkin’s and non-Hodgkin’s lymphoma, both small and non-small lung cancer, neuroblastoma, testicular cancer, thyroid cancer, Wilms’ tumor and different types of sarcomas [ 18 , 19 ]. Its action consists of the intercalation into the double-stranded DNA helix [ 20 ], inhibition of topoisomerases I and II [ 21 , 22 ], metal-ion chelation [ 23 ] and creation of free radicals [ 19 , 24 ]. Overall, DOX acts by provoking cell death by multiple mechanisms that may vary between cell types from apoptosis to necrosis [ 25 ].…”

Modulatory effects of the antioxidant ascorbic acid on the direct genotoxicity of doxorubicin in somatic cells of Drosophila melanogaster

“…Doxorubicin is also a genotoxic agent that inhibits the activity of the enzyme topoisomerase II, resulting in the accumulation of DNA strand breaks that, if not repaired by the cell, can provoke mutations and chromosomal aberrations in tumor and non-tumor cells in mammalian systems (Islaih et al, 2005;Resende et al, 2006). Cellular enzymes are capable of converting DXR into free-radical metabolites (Benchekroun et al, 1992;Menegola et al, 2001). Furthermore, a significant reduction in total plasma antioxidant capacity was observed in smallcell lung cancer patients treated with DXR (Erhola et al, 1996).…”