The effect of the nitroxide pirolin on oxidative stress induced by doxorubicin and taxanes in the rat brain.

The anticancer drugs doxorubicin (DOX), paclitaxel (PTX) and docetaxel (DTX) have been proven to induce oxidative stress (OS)-dependent side-effects in non-targeted tissues. In normal conditions, the blood-brain barrier (BBB) prevents these drugs from penetrating into the brain. However, some studies have demonstrated that small amounts of DOX can penetrate the brain via an oxidatively impaired BBB and cause damage, which suggests that including antioxidants in chemotherapy could possibly protect the brain against the toxicity of anticancer drugs. We investigated whether DOX, DTX and PTX can induce oxidative damage in rat brains in vivo and whether inclusion of the nitroxyl antioxidant Pirolin (PL) to DOX/taxane chemotherapy can protect the brain from the OS toxicity of these drugs. Wistar rats received i.p. a single dose (10 mg/kg b.w.) of DOX, DTX, PTX or PL alone or a combination of a drug + PL. After four days, the rats were anesthetized, the brains were excised, homogenized and used for the measurements of lipid peroxidation (LPO), thiol groups, activities of antioxidant enzymes, DNA damage and tumor necrosis factor-α (TNF-α), neuronal nitric oxide synthase (nNOS) and poly (ADP-ribose) polymerase-1 (PARP-1) expression. The results were analyzed using the Kruskal-Wallis and Conover-Inman tests or ANOVA and the Tukey-Kramer test. Doxorubicin, PTX and DTX induced OS, DNA damage and changes in expression of TNF-α, nNOS and PARP-1 in the rat brain. Pirolin alone increased LPO, manganese superoxide dismutase (MnSOD) and catalase (CAT) activities and the expression of PARP-1 but decreased TNF-α expression. PL, in combination with anticancer drugs, partially protected the rat brain against the toxic effects of DOX and taxanes. The best protective effects of PL were obtained with PTX. Pirolin partially attenuated brain damage caused by DOX/taxanes, highlighting its potential application in protecting the brain against DOX-, DTX- and PTX-evoked OS.

Nitroxide pirolin reduces oxidative stress generated by doxorubicin and docetaxel in blood plasma of rats bearing mammary tumor.

Combination of doxorubicin (DOX) and docetaxel (DTX) is clinically effective against many drug-refractory cancers, nevertheless, enhanced side effects, e.g. cardiotoxicity related to oxidative damage of tissue macromolecules is observed. Nitroxides represent an attractive class of synthetic compounds to ameliorate DOX-DTX toxicity in non-targeted tissues due to their antioxidant and iron-oxidizing properties. The aim of the study was to define the ability of 3-carbamoylpyrroline nitroxyl derivative pirolin (PL) to mitigate oxidative damage to blood plasma proteins and lipids induced by DOX-DTX chemotherapy in Sprague-Dawley rats bearing DMBA-induced mammary tumor. Additionally we also evaluated: i) pro-oxidant and antioxidant activity of pirolin administered as a single agent according to different regimens and ii) differences in biomarkers of the oxidative stress between healthy rats and rats with DMBA-induced mammary tumors. The extent of oxidative stress was evaluated on the basis of its foremost biomarkers: thiol and carbonyl groups, lipid peroxidation products (hydroperoxides, TBARS), activity of antioxidant defense enzyme superoxide dismutase (SOD) and non-enzymatic antioxidant capacity (NEAC). We have found that pirolin alone displayed dual, antioxidant and pro-oxidant activity depending on the regimen of treatment. Daily treatment for 2 weeks increased the amount of thiols, and decreased the protein carbonyl groups. Three administrations of pirolin at 3-week intervals did not influence thiol content but increased hydroperoxides, TBARS and carbonyl groups. Chemotherapy employing DOX-DTX combination caused considerable oxidative stress in the plasma. Significant and dose-dependent oxidative damage to lipids and proteins with concomitant thiol depletion were evident in treated animals. Drugs also increased SOD activity and NEAC. Association of pirolin with DOX-DTX chemotherapy resulted in a partial amelioration of oxidative stress generated by anticancer drugs. This study indicates that a nitroxyl compound pirolin applied as a single agent in vivo can display both antioxidant and pro-oxidant properties but in conjunction with DOX-DTX it is able to protect partially blood plasma against oxidative stress generated by chemotherapy. The outcome, however, seems to be highly dependent on the ratio between the doses of employed anticancer drugs and the nitroxide.