**Author details**

pathways which lie upstream of mitochondria and that are frequently deregulated in cancer [158]. However, the targeting of mitochondria as a therapeutic strategy is often compromised by the absence of significant pathophysiological differences between mitochondria in normal and malignant cells, leading to reduced selectivity of drugs targeting mitochondria. Therefore, the actions that are beneficial in cancer cells may, in contrast, underlie some of the severe toxic

Indeed, the induction of mitochondrial damage is an important contributor for some of the most well-known toxic effects of anticancer agents, namely the liver injury promoted by tamoxifen [159], the cardiotoxicity of doxorubicin or the cisplatin-induced neuropathy and nephrotoxicity. Organ dysfunction has a significant impact on the treatment outcomes and, therefore, the better understanding of the mechanisms of toxicity may unveil strategies to limit, or preferably to prevent, the incidence of these events and thereby improve the overall clinical

The recognition that mitochondrial dysfunction plays a key role in drug-induced toxicity may contribute to identify the drugs that are more likely to lead to such effects at an early stage. In this context, the use of isolated mitochondria fractions is a valuable tool to predict drug safety, since it provides relevant information while allowing to reduce the number of laboratory

On the other hand, our current knowledge does not allow to predict the idiosyncratic injury related with drug-induced mitochondrial dysfunction. It seems that genetic, metabolic and environmental factors that impair mitochondrial function can add their effects to those of anticancer drugs, compromising mitochondrial function to an extent where manifestations start to occur [17]. Therefore, therapeutic drug monitoring is mandatory. Furthermore, as organ damage may become apparent months or even years after the completion of the treatment (e.g. late-onset doxorubicin toxicity) the need of long-term follow-up is reinforced.

Finally, future studies should aim to develop strategies which are able to afford protection against both the short-term and long-term effects of anticancer drugs and without compro‐ mising their antitumor activity. Although antioxidants showed promise in *in vitro* studies, inconsistent results and failure in clinical trials turn the use of antioxidants as adjuvants in cancer therapy hardly consensual [7, 83]. However, in this context, we need to take into consideration that antioxidants may present different intracellular localization patterns and interfere with normal redox signaling pathways in specific cell compartments; an approach involving the targeted delivery of antioxidants to mitochondria can possibly provide better outcomes [7, 83]. Moreover, there are important differences between *in vitro* and *in vivo* toxicities and between animal models and humans. The different drug metabolism and clearance, as well as the asymmetries in redox regulation may account for the difficulty in

In conclusion, studies in suitable animal models are vital for a better understanding of the mechanisms underlying drug toxicity and the benefits of strategies aiming to prevent mito‐ chondrial damage. So far most studies have used animal models devoid of tumors, which add an extra physiological burden that may influence the effects of drugs [83]. Moreover, as

effects promoted by these agents.

42 Toxicology Studies - Cells, Drugs and Environment

animals and the costs of preclinical studies [8].

translating these strategies into human subjects [83].

success.

Mariana Ponte Cardoso Ribeiro, Armanda Emanuela Castro e Santos and José Barata Antunes Custódio\*

\*Address all correspondence to: custodio@ci.uc.pt

Center for Neuroscience and Cell Biology, Faculty of Pharmacy, University of Coimbra, Coimbra, Portugal
