**1. Introduction**

#### **1.1 Historical background**

In the 1950s Italian based company; Farmitalia research laboratory began a research program in finding the anticancer compounds from soil-based microbes. In the process of research collected a soil sample from the castle named as castle Del monte, which was built in the 13th century. The collected soil sample contains new strains of bacterial species and isolated from it. The separated microbe recognised with the name Streptomyces peucetius which is typically produces a significant red pigment. The antibiotic produced from this bacterium discovered to be efficient in treating the tumours especially solid tumours while researching on mice. Since a group of French scientists found the same compound about at the same time, they agreed to call the antibiotic daunorubicin, referring to the two nations. In which, Dauni refers to the pre-Roman tribe who inhabited the position in Italy where the species of bacteria were isolated and ruby represents the colour in Italy. The clinical trials of daunorubicin were began in 1960s and confirmed as successful in treating the lymphoma and acute leukaemia [1, 2]. After a short note of the time, in 1967 daunorubicin was discovered to be cause fatal cardiotoxicity. Then, by using nitroso-N-methyl urethane, the Italian research company mutated the strains of Streptomyces peucetius and developed a new strain of bacterial species that produces 14-hydroxylated daunorubicin, also known as Adriamycin (named after the Adriatic Sea), then changed its name to doxorubicin, which has a strong therapeutic index, but cardiac toxicity remains [3].

### **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 in neuroblastoma [7, 8].

## **2. Doxorubicin side effects**

#### **2.1 Hepatotoxicity**

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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**Figure 1.**

*DOX mediated effects on the liver.*

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

**2.2 Nephropathy**

The metabolized intermediates in the presence of oxygen converted to carbonyl moieties resulting in generation of Superoxide anions and hydrogen peroxides causes peroxidation of lipids in membranes of cell, aggregation of proteins (**Figure 1**) [13–15]. The regenerative capacity of liver is more can cure the damage caused by various agents such as DOX, which causes damage and decreases the regeneration of liver cells by increasing the oxidative stress due to the radical generation by oxidation in hepatocytes. The generated radical causes decrease in GSH levels, damages in DNA and also act as secondary metabolites in in many metabolic pathways which includes in cell proliferation and cell death [16–18]. To overcome such situations liver employs the efflux mechanisms, the efflux of DOX is achieved through from liver by ATP dependent ABC proteins (P-glycoprotein) which increase the efflux of the intracellular DOX and maintain the homeostasis. The mechanism uses large quantity of energy but with the presence of the DOX in liver cells decreases the ATP production and increases the ADP and Pi within the cells [19–21]. Due to this effect sometimes liver cells can't able

to regenerate from DOX induced effects and causes hepatotoxicity.

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

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

The metabolized intermediates in the presence of oxygen converted to carbonyl moieties resulting in generation of Superoxide anions and hydrogen peroxides causes peroxidation of lipids in membranes of cell, aggregation of proteins (**Figure 1**) [13–15].

The regenerative capacity of liver is more can cure the damage caused by various agents such as DOX, which causes damage and decreases the regeneration of liver cells by increasing the oxidative stress due to the radical generation by oxidation in hepatocytes. The generated radical causes decrease in GSH levels, damages in DNA and also act as secondary metabolites in in many metabolic pathways which includes in cell proliferation and cell death [16–18]. To overcome such situations liver employs the efflux mechanisms, the efflux of DOX is achieved through from liver by ATP dependent ABC proteins (P-glycoprotein) which increase the efflux of the intracellular DOX and maintain the homeostasis. The mechanism uses large quantity of energy but with the presence of the DOX in liver cells decreases the ATP production and increases the ADP and Pi within the cells [19–21]. Due to this effect sometimes liver cells can't able to regenerate from DOX induced effects and causes hepatotoxicity.
