**4.7. Retinoids**

All-*trans*-retinoic acid was approved in 1995 by the Food and Drug Administration for the treatment of acute promyelocytic leukemia, changing the outcome of this disease, which was associated with a significant mortality until then. Retinoids induce hepatotoxicity, either during dietary supplementation [120] or treatment of acute promyelocytic leukemia patients [121], and hypertriglyceridemia [122]. Moreover, vitamin A supplementation in rats induces slight enlargement of mitochondria [123], hepatic oxidative insult and mitochondrial dys‐ function [124], supporting the view that mitochondria are a target of retinoid toxicity.

All-*trans*-retinoic acid is a known inducer of MPT pore opening [125-127], which is thought to reflect its ability to modulate ANT activity in both liver and heart mitochondria [126]. All*trans*-retinoic acid depresses the phosphorylation efficiency of mitochondria and, at higher concentrations, induces uncoupling of mitochondria [127]. Whereas earlier studies attribute the uncoupling promoted by retinoids to an increase in the IMM permeability [128], a more recent study suggests that the leak of protons through the Fo fraction of complex V is the underlying mechanism [127]. Thus, is seems likely that the liver injury promoted by all-*trans*retinoic acid reflects its effects on mitochondria (Fig.1).

#### **4.8. Targeted therapy**

#### *4.8.1. Monoclonal antibodies*

Trastuzumab is a recombinant humanized monoclonal antibody against the human epidermal growth factor receptor 2 (HER2), which is overexpressed by many adenocarcinomas. Trastu‐ zumab improves cancer patient survival, but it also causes cardiotoxicity in a significant number of patients, ranging from 2-7 % when used as monotherapy, 2-13 % when used combined with paclitaxel, and up to 27 % when trastuzumab is used with both anthracyclines and cyclophosphamide [3]. In contrast to the cardiomyopathy promoted by doxorubicin, the cardiac dysfunction induced by trastuzumab does not appear to be dose dependent and is often reversible [123]. Neonatal rat cardiomyocytes treated with an inhibitory HER2 antibody exhibit an increased ROS production and cell death, which are reversed by N-acetylcysteine and by CyA, suggesting that the toxic effects of trastuzumab on the heart involve mitochon‐ drial damage and enhanced ROS production (Fig.1) [129].

#### *4.8.2. Tyrosine kinase inhibitors*

Sorafenib is effective against renal-cell carcinoma and hepatocellular carcinoma, whereas sunitinib is used in the management of advanced kidney cancer, gastrointestinal stromal tumor, and pancreatic neuroendocrine tumors. In phase I–II trials, 11 % of patients taking sunitinib experienced cardiovascular events and approximately half of the patients developed hypertension [130]. The incidence of sorafenib-associated heart toxicity is lower than that of sunitinib, and hypertension occurred in about 17 % of patients in clinical trials [131].

Sorafenib compromises mitochondrial function at clinically relevant concentrations in a myoblastic cell line grown under conditions where cells are either glycolytically or aerobically poised; the other tyrosine kinase inhibitors investigated (imatinib, dasatinib, sunitinib) do not affect the mitochondria [132]. Sorafenib uncouples heart mitochondria and inhibits complex V and complex II+III; at much higher concentrations the complex I and IV are also inhibited (Fig.1) [132].

Using neonatal rat cardiomyocyte cultures, it was shown that sunitinib decreases the mito‐ chondrial membrane potential, and that both sunitinib and sorafenib reduce the intracellular ATP levels [133]. Echocardiographic abnormalities are apparent in sorafenib, but not in sunitinib or pazopanib treated animals; the analysis of ventricular cardiomyocytes revealed that sunitinib promotes mitochondrial swelling, dense deposits, and matrix cavitation, whereas sorafenib disrupted mitochondrial cristae [133].

#### *4.8.3. Proteasome inhibitors*

Bortezomib is a proteasome-inhibitor approved for the treatment of multiple myeloma and mantle cell lymphoma and its use in other types of cancer is currently under investigation. However, bortezomib induces dose-limiting peripheral neuropathy and compromises complex I- and complex II-mediated respiration, as well as ATP production in peripheral nerve axons, suggesting that mitochondrial dysfunction plays a key role in bortezomib-induced peripheral neuropathy (Fig.1) [134].



exhibit an increased ROS production and cell death, which are reversed by N-acetylcysteine and by CyA, suggesting that the toxic effects of trastuzumab on the heart involve mitochon‐

Sorafenib is effective against renal-cell carcinoma and hepatocellular carcinoma, whereas sunitinib is used in the management of advanced kidney cancer, gastrointestinal stromal tumor, and pancreatic neuroendocrine tumors. In phase I–II trials, 11 % of patients taking sunitinib experienced cardiovascular events and approximately half of the patients developed hypertension [130]. The incidence of sorafenib-associated heart toxicity is lower than that of

Sorafenib compromises mitochondrial function at clinically relevant concentrations in a myoblastic cell line grown under conditions where cells are either glycolytically or aerobically poised; the other tyrosine kinase inhibitors investigated (imatinib, dasatinib, sunitinib) do not affect the mitochondria [132]. Sorafenib uncouples heart mitochondria and inhibits complex V and complex II+III; at much higher concentrations the complex I and IV are also inhibited

Using neonatal rat cardiomyocyte cultures, it was shown that sunitinib decreases the mito‐ chondrial membrane potential, and that both sunitinib and sorafenib reduce the intracellular ATP levels [133]. Echocardiographic abnormalities are apparent in sorafenib, but not in sunitinib or pazopanib treated animals; the analysis of ventricular cardiomyocytes revealed that sunitinib promotes mitochondrial swelling, dense deposits, and matrix cavitation,

Bortezomib is a proteasome-inhibitor approved for the treatment of multiple myeloma and mantle cell lymphoma and its use in other types of cancer is currently under investigation. However, bortezomib induces dose-limiting peripheral neuropathy and compromises complex I- and complex II-mediated respiration, as well as ATP production in peripheral nerve axons, suggesting that mitochondrial dysfunction plays a key role in bortezomib-induced

**Mechanism Drug class Target organ References**

All-*trans*-retinoic acid Miscellaneous agents Heart and liver [125-127] Paclitaxel Antimicrotubules Heart, liver, kidney [110]

Etoposide Enzyme inhibitors Liver [106] Cisplatin Alkylating agents Liver [71]

Doxorubicin Enzyme inhibitors Heart and brain [84, 86, 87, 94, 95, 102]

sunitinib, and hypertension occurred in about 17 % of patients in clinical trials [131].

drial damage and enhanced ROS production (Fig.1) [129].

whereas sorafenib disrupted mitochondrial cristae [133].

*4.8.2. Tyrosine kinase inhibitors*

38 Toxicology Studies - Cells, Drugs and Environment

(Fig.1) [132].

**MPT**

*MPT induction*

*4.8.3. Proteasome inhibitors*

peripheral neuropathy (Fig.1) [134].

**Table 1.** Summary of the mechanisms of mitochondrial dysfunction promoted by anticancer agents (GI, gastrointestinal tract; MPT, mitochondrial permeability transition; mtDNA, mitochondrial DNA; SERMs, selective estrogen receptors modulators).
