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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.

Sumber:http://pubchem.ncbi.nlm.nih.gov/

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 3’phosphate 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 & Gilman’s 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.

Contributors: Adam Hermawan and Sarmoko