**2.2 Nephropathy**

*Advances in Precision Medicine Oncology*

**1.2 Doxorubicin chemical structure and properties**

Doxorubicin (DOX) is an anthracycline antibiotic structurally similar to Daunorubicin as natural anti-cancer antibiotic used in cancer treatment. Its anticancer effect produced intercalating with DNA and this will inhibit DNA transcription and replication; and by binding to the topoisomerase II enzyme and inhibit the resealing of the DNA fragments. The presence of sugar moiety attached to the anthracycline ring further enhances the binding to phosphate and sugar moieties in to DNA. This led to stops the proliferation of cancer cells in the host [4]. Besides, the presence of quinone moiety apart from contributing the cytolytic ability by generating the intermediate radicals, which further react with the oxygen and forms superoxide ions and these ions also shows a high tendency towards the damaging

the cell membranes causes a dose-dependent the cardiac myopathy [5, 6].

The Doxorubicin is mainly used in case of patients suffering from Breast cancer, ovarian cancers, lung cancers, bladder cancers, leukaemia (acute lymphoblastic leukaemia, acute myeloid leukaemia) and AIDS-related Kaposi's sarcoma and various solid tumours. DOX also used in combination with other agents in case of bone sarcomas, soft tissue sarcomas, uterus cancer, endoblastoma cancer, cervix cancer, pancreatic cancer, Ewing's sarcoma, mesothelioma, multiple myeloma, Wilms tumour and

Liver is one of the essential organs of the body; it plays a major role in metabolism and detoxification of several drugs. This can explains why liver is the primary body organ affected by chemotherapy. Despite being cytostatic and cytotoxic effects on cancer cells DOX documented to accumulate in the various tissues include liver cells. In humans, it is estimated as 50% of DOX eliminated in un-exchanged form, the remainder dose metabolised through hydroxylation, semiquinone formation [9]. The major pathway for biotransformation of DOX is catalysed by the NADPH-dependent carbonyl reductase, Nitric oxide synthase, cytochrome P-450 reductase, aldo-keto reductase enzymes. The hydroxylation occurs at C-13 carbon in group commonly reaction referred as electron reduction forms the secondary alcohol metabolites [10–13].

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in neuroblastoma [7, 8].

**2.1 Hepatotoxicity**

**2. Doxorubicin side effects**

Besides maintaining the homeostasis by regulating the body fluids, kidneys work to reabsorb the low concentrations general constituents in the body and also remove the foreign substances like drugs or other kinds of agents. For this kind of reasons kidneys considered as metastatic organs of human beings [22]. The regenerative capacity of the kidneys is low when compared to the liver and highly susceptible to

**Figure 1.** *DOX mediated effects on the liver.*

epithelial degeneration occurs at renal glomerulus where the filtration occurs may lead to the glomerulosclerosis [23].

DOX interferes with the glandular podocytes of the kidney and cause nephropathy the most accepted mechanism behind the nephropathy is an accumulation of proteinuria in the kidney by the local passage of leaked proteins [23]. Increase in the structural changes in nephrons causes hypertension, steroid resistance, high incidents of renal failure and glomerular vacuolization, inflammation, tubular dilation, intestinal fibrosis, permeability differences in the glomerulus, and certain conditions like hypoalbuminemia, dyslipidemia, hypercoagulation, size differences in kidney most likely observed [24]. A study conducted on the DOX effect on the mitochondria by the Lebrecht suggested that DOX interfere the mitochondrial mtDNA in the kidney with ROS produced from it and accelerating the damaging of the nephron. Another study reports suggesting that DOX forming an iron-mediated anthracycline complex, which produces the ROS led to an increase in the oxidative lesions in the cells causing damage to the critical cellular components [25, 26].

The decreasing the levels of the GSH (Glutathione), vitamin E levels and other natural oxidant levels production from the liver cells enhances the nephropathic conditions which may initially affect the Bowman's capsule thickness and the glomerular tuft of the nephron. The study conducted by Rook et al. [26] Reported as Angiotensin-converting enzyme is said to be one of the responsible factors for tissue damage triggered by the DOX therapy. The ACE is causing the pro-inflammatory, pro-fibrotic effects which make interference in the kidney and nephrons to maintain the glomerular pressure and filtration rate of blood [27, 28]. The cases of nephropathy and proteinuria are rare in humans susceptibility towards such condition based on the genetic makeup of the individual.

#### **2.3 Neurotoxicity**

The brain is the largest and most complex organ in the human body contains about 100 billion neurons with 1 trillion established connections throughout the body. DOX is not able to transfer through the blood–brain barrier (BBB), therefore DOX effects against the brain via indirect way [29, 30]. These effects include: depression, anxiety, decrease in motor functions, haemoglobin levels, perception skills affected, and menopausal status, visuospatial skills are affected through cancer chemotherapy. The recovery of the cognitive functions may take up to a year [31]. The DOX mediate increase TNF-α level (inflammatory cytokines produced by the macrophages/monocytes during the acute inflammation involved in many signalling pathways) in the brain at cortex and hippocampus of mice [32–34]. The mitochondrial activity, glutathione-S-transferase, GSH levels, and MnSOD levels in the brain are decreased and increase in levels of 4-hydroxynoneal (HNA), thiobarbituric acid reactive substances (TBARS), malondialdehyde (MDA) and increase in levels of protein carbonyl groups [35–38], which causes increase the oxidative stress in the brain cells and further led to cause cell damage.

The MnSOD levels in the brain generally detoxify the oxygen free radicals, inactivated by the Nitric oxide (NO). The DOX indirectly increased the concentration of NO by overexpressing the Nitric oxide synthase enzyme [37]. A study conducted on the NOS dependent brain injury with DOC reinforcing the nitric oxide tissue damage [38]. The mitochondrial activity is very important in the brain because it is a powerhouse of cells (energy production) brain uses 20% of body glucose for energy production to conduct and maintain the regular activities [39]. The DOX induces generation of MDA, TBARS, and HNA which cause the decrease the mitochondrial activities. A study conducted on the DOX-induced toxicity on rats with 10 mg/kg dose, the rats died between 10 and 50 days with observed

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**Figure 2.**

*DOX-mediated effects on the Heart.*

*Overview on the Side Effects of Doxorubicin DOI: http://dx.doi.org/10.5772/intechopen.94896*

peripheral nervous system [40].

[44, 45].

**2.4 Cardiomyopathy**

>601 mg/m<sup>2</sup>

light microscopic studies reveals that specific changes in the ganglionic cells of the

This side effect found to be a dose-dependent on DOX. The DOX-induced cardiotoxicity occurs acutely and chronically. The acute effects occur within one week period the patient may experience arrhythmia, hypotension, and super ventricular tachycardia. These abnormalities are generally reversible in a noticeable period [41]. The chronic effects are shown in only 1.7% of patients with a 50% mortality rate [42, 43]. The chronic effect of DOX such as congestive heart failure reported

cause the CHF, and almost 35% of patients observed with CHF when treated with

A study conducted by the Zordosky and EI-kadi on DOX-induced toxicity reported as the induction of Brain natriuretic peptides, atrial natriuretic peptides genes, monooxygenases, cytochrome P genes and hypertrophy markers responsible for the xenobiotics and certain endogenous substances [46]. The inductions of these genes are cause cardiac hypertrophy leading to heart failure and altered the arachidonic acid mechanisms. A study reported the DOX effects based on the concentrations, at low concentrations DOX dose (o.5–1 μM) causes the alterations in structural proteins (includes sarcomeric myosin, nuclear lamina), plasma membrane blebbing (causes change in cell shape), and mitochondrial depolarization and fragmentation. At high concentration causes (5–50 μM) causes the cytoplasm vacuolization, swelling of mitochondrial cells, promote the cellular alterations (**Figure 2**) at the cellular and nuclear membranes [47]. The DOX reportedly binds

in more than

18% of patients

in a study, when the patients are treated with dose 500–550 mg/m<sup>2</sup>

4% of patients when treated with the dose is 551–600 mg/m<sup>2</sup>

light microscopic studies reveals that specific changes in the ganglionic cells of the peripheral nervous system [40].
