*2.5.4 Cell death*

The general apoptosis is a process where a cell commits to suicide, damage to genetic material, protein, cellular organelles that beyond the repair would trigger the suicide to save the energy and resources. Apoptosis firmly regulated process involves intrinsic mitochondrial apoptosis, extrinsic death receptor pathways [74]. The mitochondrial pathway relays on the Trans membrane potential is a key indicator of membrane permeability. It is assumed that permeability can be either permeability-dependent or independent of the pore transition [PT]. The PT pore consists of the adenine nucleotide translocator, matrix protein cyclophilin D, and voltage-dependent anion channel. The opening of the PT pore activates the dissipation of the proton gradient produced by electron transport, resulting in the uncoupling of oxidative phosphorylation. The opening of the PT pore also allows water to penetrate the mitochondrial matrix, resulting in the swelling of the intermembrane space and the rupturing of the outer membrane allowing the release of apoptogenic proteins. Released proteins include cytochrome c, apoptosis-inducing factor and endonuclease G. Cytochrome c in conjunction with apoptosis protease activating factor (APAF-1) and pro-caspase 9 forms an apoptosome, which in turn activates effector caspases that collectively facilitate the execution of apoptosis. Due to decrease in the number of normal cardiomyocytes is significantly reduced, the heart failed to pump the blood sequentially ventricular remodelling and death of myocytes [75].

The death receptor pathway involves the binding of death ligands such as FasL, TNF-α to their respective membrane-bound receptors. The bonded ligands signals to various proteins mediate the cascade, which leads to apoptosis of the cell [76]. In cancer therapy, DOX-induced ROS activates the p38, p53 and NF-kB pathways resulting in the differences in pro- and anti-apaptonic signalling imbalance, such imbalance cause release of cytochrome C from mitochondrial membrane proteins, subsequently lead to apoptosis of cell [77, 78].

#### *2.5.5 Autophagy*

Autophagy is a method of restoring or repairing the destroyed cells. It is a self-degrading mechanism (survival mechanism) to maintain a balance of life in response to dietary stress, energy depletion. Autophagy destroys malformed proteins, weakened organelles, and other cell infections, which can be unique or non-specific, but processes are not completely thought out. Under diseased

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

ing mitochondrial ROS formation.

latero-ventricular dysfunction.

and kawasaki heart disease [85].

cardiomyopathy [86].

cardiomyopathy.

case of doxorubicin induced cardiomyopathy.

results become a disadvantage for this technique.

**2.6 Diagnosis**

measured.

environments, autophagy either facilitates cell death or induces cell death depending on the demands of different people [79, 80]. In DOX-based therapy toxicity mediated autophagy by suppressing GTAT4 expression and activating S6K1, this plays a direct and indirect role in autophagy control. Autophagy varies due to species differences; autophagy dependent on DOX is increased in mice but decreased in autophagy has been seen in mouse cases [81–84]. The autophagy achieved in DOX therapy via several mechanisms, such as ATG 5 & 12 is the inhibitors of the Bcl-2 family, which regulate the cytochrome release from the mitochondria. Cytochrome C releases the caspase-9 lead to the autophagosome, can regulate the apoptosis. In some other studies, autophagy reduces the DOX-induced cardiotoxicity by decreas-

The DOX-induced cardiomyopathy consists of a complete examination of the cardiovascular system for detecting the symptoms, such as S3 gallop and elevated jugular vapour pressure, T wave impairments; low voltage QRS complexes are

• Electrocardiography combined with Doopler studies used to study early diagnostic symptoms of the cardiac myopathy through the measure of

• Radionuclide ventriculography used to access the latero-ventricular systolic and diastolic function. Observes the cardiac adrenergic denervation occurs in

• Metaiodobenzylguanidine based nuclear imaging can be employed to assess cardiac adrenergic denervation occurred trough the DOX based

• The DOX treated patients are sensitive to the indium labelled monoclonal antimyosin antibodies (myosin an ATP dependent superfamily of motor proteins major role in muscle contraction and motility) used to detect the cardiac myopathy, myocarditis, chagas heart disease ischemic myocardium,

• The measurement of the cardiac enzymes and neurohormones are used for detecting the heart failure but not a characteristic feature of the DOX-induced

• The presence of endomyocardial biopsy is the best route for detecting the DOX-induced diseases, according to the grade of biopsy severity of the disease is measured [87, 88]. It is invasive and requires experience for recognising the

**3. Management & preventive strategies for doxorubicin cardiotoxicity**

The DOX has an extreme side effect like cardiotoxicity, but is still in use because of its efficacy in the treatment of cancers. Toxicity can be avoided in several ways. Many studies have shown that cardioprotective agents can achieve a reduction in cardiotoxicity. A recent research on HSP-20 (heat-shock protein) has shown that the

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

environments, autophagy either facilitates cell death or induces cell death depending on the demands of different people [79, 80]. In DOX-based therapy toxicity mediated autophagy by suppressing GTAT4 expression and activating S6K1, this plays a direct and indirect role in autophagy control. Autophagy varies due to species differences; autophagy dependent on DOX is increased in mice but decreased in autophagy has been seen in mouse cases [81–84]. The autophagy achieved in DOX therapy via several mechanisms, such as ATG 5 & 12 is the inhibitors of the Bcl-2 family, which regulate the cytochrome release from the mitochondria. Cytochrome C releases the caspase-9 lead to the autophagosome, can regulate the apoptosis. In some other studies, autophagy reduces the DOX-induced cardiotoxicity by decreasing mitochondrial ROS formation.
