Oxidation of Anthracyclines by Peroxidase Metabolites of Salicylic Acid

Abstract

Oxidation of anthracyclines leads to their degradation and inactivation. This process is carried out by peroxidases in the presence of a catalytic cofactor, a good peroxidase substrate. Here, we investigated the effect of salicylic acid, a commonly used antiinflammatory and analgesic agent, on the peroxidative metabolism of anthracyclines. We report that at pharmacologically relevant concentrations, salicylic acid stimulates oxidation of daunorubicin and doxorubicin by myeloperoxidase and lactoperoxidase systems and that efficacy of the process increases markedly on changing the pH from 7 to 5. This pH dependence is positively correlated with the ease with which salicylic acid itself undergoes metabolic oxidation and involves the neutral form of the acid (pK a ϭ 2.98). When salicylic acid reacted with a peroxidase and H 2 O 2 at acid pH (anthracyclines omitted), a new metabolite with absorption maximum at 412 nm was formed. This metabolite reacted with anthracyclines causing their oxidation. It was tentatively assigned to biphenyl quinone, formed by oxidation of biphenol produced by dimerization of salicylic acid-derived phenoxyl radicals. The formation of this product was inhibited in a concentration-dependent manner by the anthracyclines, suggesting their scavenging of the salicylate phenoxyl radicals. Altogether, this study demonstrates that oxidation of anthracyclines is mediated by peroxidase metabolites of salicylic acid, such as phenoxyl radicals and the biphenol quinone. Given that cancer patients undergoing anthracycline chemotherapy may be administered salicylic acid-based drugs to control pain and fever, our results suggest that liberated salicylic acid could interfere with anticancer and/or cardiotoxic actions of the anthracyclines.Acetylsalicylic acid (aspirin, ASA) (Fig.

Antinociceptive peripheral effect of Achillea millefolium L. and Artemisia vulgaris L.: both plants known popularly by brand names of analgesic drugs

“…o-Hydroxybenzoic acid (salicylic acid) is commonly used as an antiinflammatory and analgesic agent (Reszka et al, 2005). Its derivative aspirin (acetyl salicylic acid) has long been used as a classic analgesic.…”

Inactivation of Anthracyclines by Serum Heme Proteins

“…We have previously reported that human promyelocytic leukemia HL-60 cells, which are rich in MPO, as well as isolated MPO and LPO enzymes, catalyze oxidation of anthracycline anticancer drugs in the presence of H 2 O 2 . A facilitating cofactor in this reaction is NO 2 - ( , ); acetaminophen and salicylic acid also enhance the reaction ( , ). This peroxidase-dependent metabolism causes inactivation of the anthracyclines as evidenced by their suppressed in vitro toxicity in human leukemia HL-60 cells, human prostate cancer PC3 cells, and rat cardiac H9c2 myocytes ( , ).…”

The electrochemistry of quinizarin revealed through its mediated reduction of oxygen

“…1B). Biologically this reaction is known to occur both directly via oxidation through a peroxidase (30) or alternatively indirectly via the oxidized products of the enzymes (31,32). Further it has been proposed that the oxidative degradation pathway of the anthracycline species may provide a possible route by which cardiac protection may be attained (8).…”