**4. Doxorubicin: anticancer antibiotics**

have still kept going to fight various severe diseases related to chemotherapeutic agents. The clinic utilization of drug is limited due to its side effects. When the molecular mechanism of the chemotherapeutic drug's side effects is clarified, it will be possible to manage all side effects. Hopefully, DOX may be able to improve the lifespan of cancer patients, which is why the purpose of the present chapter is to summarize its toxic effects on cardiac

Cancer has a very high mortality and morbidity rate worldwide [1, 2] and is scaling up every year. In 2012 14 million people were diagnosed with cancer and 8.2 million people died due to cancer and cancer-associated diseases [3]. It is estimated that these figures will double by the year 2030 [4]. Patients are treated with radiotherapy, chemotherapy, and combination therapy. However, radiotherapy has been reported to be toxic and chemotherapy has been suggested to partially reduce the number of side effects. So, a chemotherapeutic agent is preferred to cure cancer [2]. Chemotherapy considerably enhances the survival rate of cancer patients. But, it is recognized to lead to side effect such as cardiovascular disease after growing survival population of a cancer patient with chemotherapy [5]. Therefore, cardiovascular diseases induced by chemotherapy are associated with high morbidity and mortality. The issue of heart damage caused by chemotherapy is a top priority due to the elevated cancer population treated with chemotherapy [6]. Anthracycline antibiotic groups are one of chemotherapeutic agents that is widely used in the treatment of solid and hematological cancer [7]. It has been indicated that the 5-year survival rate of childhood cancer patients was 30% before the discovery of group agents. However, this rate is around 80% today [8]. Still, extensive

Anthracycline antibiotics include DOX, daunorubicin, epirubicin, and idarubicin (**Figure 1**) [9]. DOX and daunorubicin are natural syntheses from *Streptomyces*, although epirubicin and idarubicin are synthetic derivatives from natural products [10]. Anthracyclines have a very high survival rate (~75%) within childhood cancer patients [11]. The drugs have been well recognized as a potential treatment against hematological cancers, including leukemias, lymphomas, solid carcinomas, and sarcomas [10, 12]. All these drugs have been reported to cause cardiotoxicity, classified as an acute and chronic effect [10]. Intracellular anthracycline tends to accumulate in the nucleus at the drug-sensitive cancer cell. However, the drug-resistant cancer cells have been outlined to find the chemotherapic agent at the cytoplasm [10]. Although some mechanism is proposed to explain the molecular structure, including oxidative stress, mitochondrial DNA (mtDNA) damage, etc., the molecular base of anthracycline on noncancerous tissue is still a mystery [12]. Because DOX is the most toxic drug in its class this chapter will evaluate only DOX toxicity, in particular heart

mitochondria.

324 Mitochondrial Diseases

damage [10].

**2. Cancer: a modern epidemic**

studies report that the group causes cardiotoxicity [6].

**3. Anthracycline chemotherapy agents**

DOX was discovered by Farmitalia Research Laboratories, and they gave it the name Adriamycin after the Adriatic Sea [14]. So, DOX is also known as Adriamycin [15], discovered from *Streptomyces peucetius* (*Streptomyces peucetius* var. *caesius*) in 1967 [16–18]; however, some studies said it was discovered in 1969 [4, 13], and its clinical utilization began in the 1970s [13] after approved in 1974 by the US Food and Drug Administration [19]. DOX is a nonselective class-I anthracyline antibiotic [20]. It has positively charged groups, mannose amine, so that the drug can efficiently bind to a negatively charged molecule, such as nucleic acid. The standard cure is in the drug range 10–50 mg/m2 [18].

DOX has been widely used in the treatment of human and nonhuman tumors, including leukemia [15], lymphomas, soft tissue sarcomas, and solid cancer [21], e.g., breast tumors, osteosarcomas, Kaposi's sarcoma, Hodgkin's and non-Hodkin's lymphomas [14, 22], thyroid and lung carcinomas, stomach, breast, bone, and ovarian cancers [23]. DOX is used for the treatment of solid childhood tumors too, such as non-Hodgkin's lymphomas, Hodgkin's disease, and soft tissue sarcomas [22].

DOX has been administered by intravenous infusion [13]. Peak plasma concentration and halflife have been reported to be 5–15 μmol/L and 20–30 h, respectively [13]. Another study, however, stated that the peak plasma concentration of patients treated with DOX is between 2 and 6 μM after bolus injection, but typically 1–2 μM [24]. DOX is reported to be very low when bound to plasma proteins [25]. The plasma clearance of DOX is measured between 324 and 809 mL/min/m2 , dominantly by biliary excretion; the maximum volume is around 809–1214 L/m<sup>2</sup> . Moreover, the half-life of the drug is around 5 min, which means that reuptake velocity is very high for tissues. However, elimination velocity is slow within the range 20–48 h [26]. After injection, DOX is disseminated to the heart, liver, kidneys, and intestine [25].

activities very are different to each other. How DOX intercalates DNA is related to the drug's chemical structure, including its chromophore's hydroxyl and daunosamine sugar's amino

Mitochondrial Dysfunction Associated with Doxorubicin http://dx.doi.org/10.5772/intechopen.80284 327

It is agreed that the mechanism of its anticancer activity and its toxic impact follow different molecular mechanisms [13, 28, 29]. The anticancer activity of DOX relies on the interaction of the cell nucleus, mitochondria, and membranes. There are a number of reasons that explain

**1.** DOX intercalates the DNA double strand, causing DNA replication and protein synthesis

**2.** Reactive oxygen species (ROS) are produced, leading to the destruction of DNA and eleva-

The anticancer effect of DOX is associated with intercalation of the DNA strands, regulatory protein, covalent binding to DNA, and condensation of histone protein. However, its toxic

The therapeutic effects of DOX have been associated with binding and intercalation of DNA strands, resulting in the destruction of replication and transcription of DNA by topoisomerase inhibition [4, 13, 30]. The reason why enzymes are so crucial is because TOPII has a role to play in modulating the DNA superhelical state [31], relaxing accumulated positive supercoils, and unlinking intertwined DNA strands. Thus, proteins are vital for complete DNA replica-

Also, DOX's cardiotoxicity has been related to disrupting TOPIIβ [30]. DOX selects toxic cardiac mitochondria through selective accumulation and redox cycling. However, free DOX enters the nuclei of cancer cells without entering mitochondria, which causes lack of mitochondrial pathway therapy [31]. Besides nuclear DNA, DOX intercalates with the mtDNA double helix, binds to a protein, and has a role in DNA replication and transcrip-

To give more detailed knowledge on drug intercalation, DOX is one of the great anticancer drugs that kills cancerous cells by interaction with the cells' DNA; it also produces covalent adducts, resulting in inhibition of DNA synthesis by DNA polymerase blocking. DOX could also interfere with DNA and TOPIIα, finally forming a TOPIIα/DOX/DNA complex. The interruption of DNA and TOPIIα by DOX causes DNA breakage and cell death. A special

**4.** DNA strands become obstructed and divided and there is helices activity.

**6.** Prevention of topoisomerase II (TOPII) results in elevation of DNA damage [17].

groups [22] (**Figure 2**).

inhibition.

tion [22].

tion as well [23].

tion of lipid peroxidation.

**5.** The membrane structure is affected.

**4.2. The mechanism of doxorubicin's anticancer activity**

the antineoplastic efficiency of the drug [17]:

**3.** DNA is cross-linked and subject to alkylation.

impact on tissue does not rely on DNA impact [15].
