Free radical mediated oxidative stress and toxic side effects in brain induced by the anti cancer drug adriamycin: insight into chemobrain.
Adriamycin (ADR) is a chemotherapeutic agent useful in treating various cancers. ADR is a quinone-containing anthracycline chemotherapeutic and is known to produce reactive oxygen species (ROS) in heart. Application of this drug can have serious side effects in various tissues, including brain, apart from the known cardiotoxic side effects, which limit the successful use of this drug in treatment of cancer. Neurons treated with ADR demonstrate significant protein oxidation and lipid peroxidation. Patients under treatment with this drug often complain of forgetfulness, lack of concentration, dizziness (collectively called somnolence or sometimes called chemobrain). In this study, we tested the hypothesis that ADR induces oxidative stress in brain. Accordingly, we examined the in vivo levels of brain protein oxidation and lipid peroxidation induced by i.p. injection of ADR. We also measured levels of the multidrug resistance-associated protein (MRP1) in brain isolated from ADR- or saline-injected mice. MRP1 mediates ATP-dependent export of cytotoxic organic anions, glutathione S-conjugates and sulphates. The current results demonstrated a significant increase in levels of protein oxidation and lipid peroxidation and increased expression of MRP1 in brain isolated from mice, 72 h post i.p injection of ADR. These results are discussed with reference to potential use of this redox cycling chemotheraputic agent in the treatement of cancer and its chemobrain side effect in brain.
Joshi
Gururaj
G
Department of Chemistry, University of Kentucky, Lexington, 40506, USA.
Sultana
Rukhsana
R
Tangpong
Jitbanjong
J
Cole
Marsha Paulette
MP
St Clair
Daret K
DK
Vore
Mary
M
Estus
Steven
S
Butterfield
D Allan
DA
D000447:Aldehydes / Q000737:chemistry; D000818:Animals; D000838:Anions; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology* / Q000633:toxicity*; D015153:Blotting, Western; D001921:Brain / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology*; D004317:Doxorubicin / Q000494:pharmacology* / Q000633:toxicity*; D005609:Free Radicals; D005982:Glutathione Transferase / Q000378:metabolism; D006801:Humans; D007477:Ions; D015227:Lipid Peroxidation; D008297:Male; D051379:Mice; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000378:metabolism; D010084:Oxidation-Reduction; D018384:Oxidative Stress; D010100:Oxygen / Q000737:chemistry; D011506:Proteins / Q000737:chemistry; D017382:Reactive Oxygen Species; D013997:Time Factors; D014443:Tyrosine / Q000031:analogs & derivatives / Q000737:chemistry
D000447:Aldehydes; D000838:Anions; D000903:Antibiotics, Antineoplastic; D004317:Doxorubicin; D005609:Free Radicals; D005982:Glutathione Transferase; D007477:Ions; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D010100:Oxygen; D011506:Proteins; D017382:Reactive Oxygen Species; D014443:Tyrosine; C002744:3-nitrotyrosine; C027576:4-hydroxy-2-nonenal; C421109:multidrug resistance-associated protein 1