Doxorubicin

Doxorubicin is an anthracycline antibiotic class which is widely used for therapy of various
cancer type line acute leukemia, breast cancer, bone and ovarian cancer (Childs et al., 2002).
This compound was isolated from Streptomyces peucetius var caesius in 1960s and was used
widely (Minotti et al., 2004). Doxorubicin cause cardio-toxicity in long-term use, it cause its
use in clinical become limited. The side effect in chronic use is irreversible, include the
formed of cardiomyopathy and congestive heart failure (Han et al., 2008). Generally
doxorubicin is used in combination form with other anticancer agent like cyclophosphamide,
cisplatin, and 5-FU. Clinical response enhancement and side effect reduction tend to be better
in using combination with other agent than using single doxorubicin (Bruton et al., 2005).
Therefore, anticancer agent development with low side effect or combination agent that can
decrease doxorubicin side effect still need to be pursued.

Souce:http://pubchem.ncbi.nlm.nih.gov/
Figure.Chemical structure of doxorubicin
Various researches about doxorubicin work mechanism have done. Anthracyclin antibiotic
like doxorubicin has cytotoxic action mechanism through four mechanism, that are:
(1) Inhibition of topoisomerase II
(2) Intercalation of DNA so that cause DNA and RNA synthesis inhibition.
(3) Cell membrane binding which cause ion flow and transport.
(4) Formation of semiquinon free radicals and oxygen free radicals through iron dependent
processes and reductive process that is mediated enzyme. This free radicals mechanism has
known responsible in cardiotoxicity cause antracyclin antibiotic (Bruton et al, 2005).
Doxorubicin can intercalation with DNA, it will directly affect transcription and replication.
Doxorubicin can form complex tripartite with topoisomerase II and DNA. Topoisomerase II
is an enzyme dependent ATP that work to bind DNA and cause double-stand break in the tip
3phosphate so that allowing strand exchange and streamlining the supercoiled DNA. The
streamlining of this strand is followed by connecting DNA strand by topoisomerase II. This
topoisomerase has very important function in DNA replication and repair. Tripartite complex
forming will inhibit DNA strand connection again, it cause inhibit of cell cycle stopped in G1
and G2 phase also accelerate the apoptosis (Gewirtz, 1999; Minotti et al., 2004). Disturbance
of the DNA repair system, whereas transcription over-expression for DNA repair may be
involved in medicine resistance phenomenon. Doxorubicin with its quinone group also can
produce good free radicals in normal cells as well as cancer cells (Gewirtz, 1999).
Doxorubicin can forming intermediate radical semiquinone, which can reacted with oxygen
to produce superoxide anion radical, which then will produce hydrogen peroxide and
hydroxyl radical that attack DNA (Serrano et al., 1999) and oxidize bases in DNA. This free
radical forming stimulated significantly by interaction between doxorubicin and iron.
Enzymatic defense in the cell like superoxide dismutase and catalase are the important thing
to maintain cell from doxorubicin toxicity (Bruton et al., 2005).
Doxorubicin toxicity mechanism has known widely. Doxorubicin cronical toxicity may be
mediated by doxorubicin metabolic conversion to be doxorubicinol which involve various
enzymes that is carbonyl reductase. Main mechanism of doxorubicinol toxicity happen
because its interaction with iron and reactive oxygen species (ROS) forming that corrupt
macromolecule cells (Minotti et al, 2004).
The happened of cardiomyopathy in doxorubicin using may be also happen because the
enhancement of oxidant produce in cardiac. Mitochondria estimated become the main target
cardiotoxicity caused doxorubicin. In mitochondria single electron was transferred to
doxorubicin so that cause enhancement of oxygen radical forming through semiquinon
doxorubicin auto-oxidation. Hydrogen peroxide also become cause of oxidative stress and
responsible to apoptosis induction by doxorubicin in endothelial cell and cardiac muscle
cells. Further, mitochondria play a role in apoptosis setting through cytochrome c discharge
(Bruton et al., 2005).
In addition to the side effect of doxorubicin use also show decline in its efficacy in cancer
therapy because medicine resistance therapy. Mechanism that causing doxorubicin resistance
is over-expression PgP that cause doxorubicin is pumped out of the cell and concentration of
doxorubicin in the cell become down. Other bio-chemical changing in doxorubicin resistance
cell that are enhancement of peroxide glutathione activity, enhancement of activity as well as
topoisomerase II mutation, also enhancement of sell ability to repair DNA damage (Bruton et
al., 2005). Therefore necessary an agent that capable to overcome doxorubicin resistance
problem also reduce side effect of doxorubicin use.
References
Bruton, L., Lazo, J. S., and Parker, K. L., 2005, Goodman & Gilmans The Pharmacological
Basis of Therapeutics, 11th Edition, McGrawHill, Lange.
Childs, A.C., Phaneuf, S.L., Dirks, A.J., Phillips, T., and Leeuwenburgh, 2002, Doxorubicin
Treatment in Vivo Causes Cytochrome c Release and Cardiomyocyte Apoptosis, As Well As
Increased Mitochondrial Efficiency, Superoxide Dismutase Activity, and Bcl-2:Bax Ratio,
Cancer Research, 62:4592-4598.
Gewirtz, D.A., 1999, A critical evaluation of the mechanisms of action proposed for the
antitumor effects of the anthracycline antibiotics adriamycin and daunorubicin, Biochem.
Pharmacol., 57:727-741.
Han, X., Pan, J., Ren, D., Cheng, Y., Fan, P., and Lou, H., 2008, Naringenin-7-O-glucoside
protects against doxorubicin-induced toxicity in H9c2 cardiomyocytes by induction of
endogenous antioxidant enzymes, Food and Chemical Toxicology, 46:3140-3146.
Minotti, G., Menna, P., Salvatorelli, E., Cairo,G., and Gianni, L. 2004. Anthracyclins:
Molecular Advances and Pharmacologic Developments in Antitumor Activity and
Cardiotoxicity. Pharmacol Rev., 56:185-228.