No abstract

Adriamycin (ADR), a potent anti-tumor agent, produces reactive oxygen species (ROS) in cardiac tissue. Treatment with ADR is dose-limited by cardiotoxicity. However, the effect of ADR in the other tissues, including the brain, is unclear because ADR does not pass the blood-brain barrier. Some cancer patients receiving ADR treatment develop a transient memory loss, inability to handle complex tasks etc., often referred to by patients as chemobrain. We previously demonstrated that ADR causes CNS toxicity, in part, via systemic release of cytokines and subsequent generation of reactive oxygen and nitrogen species (RONS) in the brain. Here, we demonstrate that treatment with ADR led to an increased circulating level of tumor necrosis factor-alpha in wild-type mice and in mice deficient in the inducible form of nitric oxide (iNOSKO). However, the decline in mitochondrial respiration and mitochondrial protein nitration after ADR treatment was observed only in wild-type mice, not in the iNOSKO mice. Importantly, the activity of a major mitochondrial antioxidant enzyme, manganese superoxide dismutase (MnSOD), was reduced and the protein was nitrated. Together, these results suggest that NO is an important mediator, coupling the effect of ADR with cytokine production and subsequent activation of iNOS expression. We also identified the mitochondrion as an important target of ADR-induced NO-mediated CNS injury. Keywords: adriamycin-induced chemobrain, central nervous system toxicity, inducible nitric oxide synthase knockout mice, manganese superoxide dismutase, mitochondrial respiration, nitric oxide. Adriamycin (ADR), a prominent member of the anthracycline family, is an important therapeutic agent that has exhibited activity against a wide spectrum of human and experimental animal tumors. It is well established that ADR leads to generation of free radicals, which account for some of the normal tissue damage resulting from cancer treatment (Meredith and Reed 1983;Licinio 1997;Singal et al. 2000). This process may result from the redox cycling capability of anthracycline, its potential to bind nitric oxide (VasquezVivar et al. 1999;Weinstein et al. 2000;Kalivendi et al. 2001;Kalyanaraman et al. 2002) Abbreviations used: ADR, adriamycin; CuZnSOD, copper-zinc superoxide dismutase; DPTA NONOate, dipropylenetriamine NONOate; iNOS, inducible nitric oxide; iNOSKO, mice deficient in the inducible form of nitric oxide; L-NAME, NG-nitro-L-arginine-methyl ester; LPS, lipopolysaccharide; MnSOD, manganese superoxide dismutase; NO, nitric oxide; ONOO -, peroxynitrite; RCR, respiration control ratio; RNS, reactive nitrogen species; RONS, reactive oxygen and nitrogen species; ROS, reactive oxygen species; TNF-a, tumor necrosis factor alpha.

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.