When DNA damage is intensive, or
the cell does not have the ability to repair DNA using restoration mechanisms
in the cell, the cell will programme itself to undergo a controlled cell death
known as Apoptosis. Furthermore, oxidative stress changes the internal
environment, as oxygen obtaining number of free radicals that can also induce
apoptosis. This occurs when Reactive oxygen species (ROS) such superoxide
anion, hydrogen peroxide and hydroxide molecules are highly concentrated in the
cell. Apoptosis further causes the dysfunction of mitochondria. Cardiotoxicity
is caused by DNA damage, ROS and mitochondrial dysfunction which are all orchestrated
by doxorubicin.

Doxorubicin is known for
anti-cancer properties clinically, this is because it interacts with the DNA of
cancerous cells. After Topoisomerase I has broken the double helix bond,
Topoisomerase II ability to seal the strands together is inhibited by
Doxorubicin, hence interrupting the process of replication. This increase the
p53 concentration this gene induces apoptosis of the cell, in addition FAS
Ligand interactions that further causes cell death. Furthermore, Poly
ADP-ribose Polymerase (PARP) concentration decreases, hence the process of
conformational binding of bases to repair the DNA cannot occur. Overall
preventing the duplication of tumour cells in the body, this can possibly affect
the cardiomyocytes. For example, fewer genes will be expressed that code for
cardiac cell type mechanisms hence the regulation and maintenance of the
cardiac system can be compromised. This includes a reduction of protein
synthesis that are important for the function contraction such actin, myosin
and ATPase, therefore contraction ability is weakened, and generation of ATPase
is reduced. The actin-myosin cross bridge can not form without ATP hence the sarcolemma
is unable to stretch to generate tension of contraction, thus the cardiac output
decrease. Although, Doxorubicin can undergo
redox reactions and produce free radicals, this injury’s the cells. Semiquinone
is an unstable product formed from the oxidation of Doxorubicin, hence the
reduction of Semiquinone is favoured which produces reactive species. This
oxidative stress cause lipid peroxidation and effects other macromolecules thus
further damaging DNA and cardiomyocytes.  Oxidative stress activates Mitogen-activated
protein kinase pathways this include p38a and c-Jun N-terminal Kinases both
involved in cell death.

Mitochondria purpose is to
synthesize ATP through the process of oxidative-phosphorylation. Mitochondria
present in cardiac myocytes are organised to generate ATP at maximum level to
efficiently supply energy for the continuous contraction of the chambers. Apoptosis
effects the mitochondria, by stimulating pro-apoptotic proteins known as BCL2
this increases the permeability of the outer membrane. This allows the movement
of Cytochrome C into the cytoplasm from the inter-membrane space. Cytochrome C
has the important role of transporting electrons between complex III and
complex IV however also involved in apoptosis. Cytochrome C activates Caspase
which activates pathways of reaction which break down proteins, such as
nuclease which breaks down DNA.

The effects of doxorubicin on
cardiac system can present in the changes present in an ECG. This in vivo
research was done on rats, that received a total of 20mg/kg divided equally
over 4 weeks, or 2 mg/kg daily for 5 days of doxorubicin. The findings show
that there was lengthened ST interval. However, changes occur on the to the QRS
interval that is prolongation, after the first few days of administration of
the drug and is reversible