**1. Introduction**

Cancer will become a major cause of morbidity and mortality in the next decades. It is estimated that the global cancer rate may increase by 75 %, with predicted 22.2 million new cases by 2030 compared with 12.7 million cases in 2008 [1]. The scientific community has made tremendous efforts to develop new therapies to deal effectively with this growing problem. As the recent advances in cancer therapy are improving the cancer patient survival, the toxic effects promoted by anticancer agents have a higher potential impact on long-term outcomes.

Anticancer agents are known to cause severe toxic effects that should be anticipated and carefully monitored. Therapeutic regimens targeting the cell cycle also affect the prolifera‐ tion of normal cells, such as blood cells in the bone marrow, cells in the digestive tract and hair follicles, resulting in neutropenia, hair loss, and gut toxicity. The side effects ob‐ served are dependent on the type of therapy, but they are generally reversible and disappear after the end of the treatment. However, some anticancer agents may also affect, some‐ times in a permanent manner, the function of vital organs, such as the heart, kidney, liver and the nervous system. Some of these effects may develop during or shortly after treatment, or may only become apparent a long period after completion of the treatment; if this delay is long enough, it may correspond to the time of progression free survival and affect the benefit-risk balance [2, 3].

Both the liver and kidneys are vulnerable to the toxic effects of cancer therapy and also to the direct impact of cancer itself. The liver has a great capacity to resist injury and to regenerate, but this capacity also makes it susceptible to anticancer drugs toxicity [2]. Indeed, the liver

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injury induced by anticancer drugs is a significant cause of morbidity and mortality. However, most of these reactions are idiosyncratic and are not typically dose-dependent [2, 4]. Diagnos‐ ing liver damage due to anticancer agents is particularly challenging because competing etiologies, such as hepatotoxicity due to the intake of other medications, opportunistic infections, radiation therapy, and pre-existing liver disease, are frequent and greatly affect the host's susceptibility to liver injury [2, 4]. The major mechanisms underlying chemotherapyrelated hepatotoxicity are based on the production of reactive metabolites, immunological injury, or mitochondrial dysfunction [4]. On the other hand, the spectrum of cancer-associated renal disease has changed in the last decades, mainly due to the introduction of new chemo‐ radiotherapy regimens. Nevertheless, renal failure remains an important complication of cancer treatment [5, 6]. Considering that drugs are primarily metabolized in the liver and excreted by the kidneys, hepatic and renal impairment can have an unpredictable impact on the metabolism and clearance of drugs that may ultimately affect the treatment outcome and toxicity.

In addition, cardiotoxicity is a common complication not only related to conventional cancer therapy, such as anthracyclines, but also to new antitumoral targeted therapy, such as trastuzumab. Due to the increasing number of patients treated with these agents, the incidence of cardiotoxicity is continuously growing and strongly affecting the patients' quality of life and overall survival, regardless of the oncologic prognosis [3]. Also, peripheral neuropathy is reported by 30-40 % of the patients and is one of the major reasons responsible for cessation of treatment [7]. Certain structural and functional features of peripheral nervous system make it more vulnerable to the action of anticancer drugs, namely the absence of a vascular barrier and of lymph drainage [7]. Furthermore, mammalian nerves are more susceptible to oxidative stress because of their high content of phospholipids, mitochondria rich axoplasm and weak cellular antioxidant defenses. Moreover, the enhanced free radical production promoted by anticancer drugs causes physical damage to neurons [7].

A thorough understanding of the mechanisms of injury is therefore a matter of great impor‐ tance since it may contribute to detect toxic mechanisms at an early stage of drug development and, importantly, it can contribute to develop strategies aiming to minimize the toxicity. Mitochondrial dysfunction often underlies drug-induced toxicity and the works published over the last years point out that some of the severe adverse effects promoted by anticancer agents involve the targeting of mitochondria [8-11]. The heart, the kidneys, and the central nervous system, which have high energetic demands and are heavily dependent on oxidative phosphorylation, are more prone to the impact of mitochondrial damage. On the other hand, considering the exposure to high concentrations of drugs, the liver is another common organ showing mitochondrial dysfunction [12].

This chapter aims to provide an overview of the mechanisms of mitochondrial dysfunction induced by anticancer drugs and their involvement in several adverse effects, and particularly liver damage. Finally, possible combinations of therapeutic drugs to minimize the mitochon‐ drial dysfunction promoted by these agents are discussed.
