| Chemotherapy is the treatment that most cancer patients receive, despite its known toxic effect on normal tissues. Cardiac injury and peripheral neuropathy are considered the most serious of the twelve most clinically relevant toxicities observed in chemotherapy-treated patients. Doxorubicin (DOX) and paclitaxel (PTX) are highly effective chemotherapeutic agents that are dose-restricted due to their cardiac and neurotoxic effects, respectively. Although extensive literature is dedicated to elucidating the mechanisms of action in both of these toxicities, neither has been completely elucidated. The roles of oxidative stress and the tumor suppressor protein p53 have been documented in DOX-induced cardiac injury and have been implicated in PTX-induced peripheral neuropathy, but to a lesser extent. The present study addresses the possibility that p53 may play a role in the toxicities of both DOX and PTX by causing oxidative stress in cardiac and neuronal tissues. DOX-induced cardiac toxicity was examined in p53 homozygous knockout (p53 (-/-)) mice and their wild-type (WT) littermates. Initial observations revealed that cardiac function and tissue integrity was not affected by the absence of the p53 protein. Despite this, p53(-/-) mice showed moderately higher basal levels of the oxidative stress marker 4-HNE in mitochondria and cytoplasm, and lower activity of glutathione-S-transferase, (GST) than WT mice. A significant reduction of cardiac function and GST activity, as well as increases in ultrastructural pathology, mitochondrial and cytoplasm levels of 4-HNE, and activities of glutathione peroxidase and catalase, were observed exclusively or in a much higher extent in DOX-treated WT mice compared to p53(-/-) mice similarly treated. PTX-induced neurotoxicity was examined in SK-N-SH cells, where we suggest that p53 translocation to the mitochondria causes inactivation of the primary antioxidant enzyme MnSOD via a direct interaction in mitochondria after PTX treatment. Specific inhibition of p53 translocation to mitochondria, but not nuclei, had a protective effect against cellular injury and MnSOD inactivation after PTX. Taken together, these results demonstrate a negative role of p53 in a DOX-induced cardiac injury model in vivo, and establish the protective effect of the inhibition of p53 translocation to mitochondria against PTX-induced neurotoxicity in vitro.;KEYWORDS: p53, oxidative stress, chemotherapy, neurotoxicity, cardiotoxicity... |
