Doxorubicin cardiotoxicity

Doxorubicin is an effective chemotherapeutic agent against multiple types of malignancies.^[1] Despite its efficacy, a well-known side effect of Doxorubicin is the cumulative, irreversible cardiotoxicity that accompanies it.^[2] The most accepted theory has suggested that the cardiotoxicity is due to increased oxidative stress in the cardiomyocytes.^[2][3][4] Since Doxorubicin is a quinone, redox reactions can generate large amount of reactive oxygen species (ROS), including superoxide (O−
2),H₂O₂, and OH⁻.^[2] These ROS then cause lipid peroxidation to biomolecules, including the plasma membrane, which is the signal for the cell to begin the apoptotic transduction pathway, specifically due to phosphatiditylserine (PS), a phospholipid membrane component, flipping from the cytosolic side of the plasma membrane to the extracellular side.^[5]

Doxorubicin-induced cardiomyopathy typically has the morphological and functional abnormalities as that of dilated cardiomyopathy, with all four cardiac chambers being dilated. Consequently, ventricular ejection fraction and contractile function is reduced, leading to diastolic dysfunction. Eventually, congestive heart failure can result, which carries a 50% mortality rate.^[6]

Significant research has gone into finding ways to attenuate Doxorubicin-mediated cardiotoxicity. Specifically, agents that may decrease oxidative stress have been considered and tested in animal models, including antioxidants like (-)-Epigallocatechin-3-gallate (EGCG), the most abundant polyphenol in green tea.^[2] A 2006 study demonstrated the general cardioprotective effects of EGCG against cardiac hypertrophy, a common pathology of the heart. The researchers tested how treatment with EGCG at varying concentrations affected the hypertrophic cardiomyocytes in rats, specifically looking at various indicators of cardiomyocyte injury, including cell viability, levels of lactate dehydrogenase and malondialdehyde, as well as the rate of apoptosis. In all of these assays, treatment with EGCG significantly reduced the incidence of cardiomyocyte injury, as well as the rate of apoptosis in a dose-dependent manner, as compared to the hypertrophic cardiomyocytes alone. Additionally, the researchers found that EGCG increased the expression levels of the antioxidant enzymes MnSOD and glutathione peroxidase in the cardiomyocytes. Furthermore, the researchers tested how the expression levels of Bcl-2 and its transcriptional modulator, tumor suppressor protein p53, were affected by the presence of EGCG, their interaction being critical to the facilitation of apoptosis. Here, the researchers found that the presence of EGCG significantly downregulated p53 expression, while it upregulated Bcl-2 expression. These results led the researchers to hypothesize that inhibition of apoptosis in Doxorubicin-treated cardiomyocytes was due to Bcl-2 acting as an antioxidant enzyme to decrease the amount of ROS, therefore inhibiting the ability of p53 to induce apoptosis.^[7] This generalized study opened the door for other groups to test the effects of EGCG on more specific cardiac dysfunctions, including the cardiotoxicity caused by Doxorubicin treatment. A 2010 study produced analogous results in the cardioprotective abilities of EGCG, testing the same indicators of cardiomyocyte injury, as well as endogenous antioxidant function, but specifically against Doxorubicin-induced cardiotoxicity. The researchers in this group, however, did not look towards as the proposed antioxidant function of Bcl-2 as being the underlying cardioprotective mechanism, instead suggesting that the enhancement of the expression of MnSOD, glutathione peroxidase, and catalase was the mechanism for the attenuation of apoptosis.^[2] Despite the differences in proposed mechanisms, both ultimately involve antioxidant activity as being the key to the reduction of apoptosis.

Despite the progress being made in finding ways to potentially prevent Doxorubicin-induced cardiotoxicity in animal models, there remains to be an effective treatment against established cardiomyopathy caused by the drug.^[6]

References

1. Allen, A. "The Cardiotoxicity of Chemotherapeutic Drugs" Semin. Oncol. 1992, 19, 529-542.
2. Todorova V. K.; Kaufmann Y.; Hennings L.; Klimberg V. S. (2010). "Oral glutamine protects against acute doxorubicin-induced cardiotoxicity of tumor-bearing rats.". Journal of Nutrition. 140 (1): 44–48. doi:10.3945/jn.109.113415. PMID 19889810.
3. Danz, E. D.; Skramsted, J.; Henry, N.; Bennett, J. A.; Keller, R. S. "Resveratrol prevents doxorubicin cardiotoxicity through mitochondrial stabilization and the Sirt 1 pathway" Free Radical Biol. Med. 2009, 46, 1589–1597.
4. Elizabeth D. Brookins Danz,; Jeremy Skramsted; Nicholas Henry; James A. Bennett; Rebecca S. Keller (June 15, 2009). "Resveratrol prevents doxorubicin cardiotoxicity through mitochondrial stabilization and the Sirt1 pathway". Free Radical Biology and Medicine. 46 (12): 1589–1597. doi:10.1016/j.freeradbiomed.2009.03.011. Retrieved 25 May 2016.
5. Joji Nitobe; Seiji Yamaguchi; Masaki Okuyama; Naoki Nozaki; Masataka Sata; Takuya Miyamoto; Yasuchika Takeishi; Isao Kubota; Hitonobu Tomoike (January 2003). "Reactive oxygen species regulate FLICE inhibitory protein (FLIP) and susceptibility to Fas-mediated apoptosis in cardiac myocytes.". Cardiovascular Research. Oxford Journals. 57 (1): 119–128. doi:10.1016/S0008-6363(02)00646-6. Retrieved 25 May 2016.
6. Kanu Chatterjee; Jianqing Zhang; Norman Honbo; Joel S. Karliner (2010). "Doxorubicin Cardiomyopathy". Cardiology. 115 (2): 155–162. doi:10.1159/000265166. PMC 2848530. PMID 20016174. Retrieved 25 May 2016.
7. Zhen-lun Gu; Mei-lin Xie; Wen-xuan Zhou; Ci-yi Guo (2007). "EGCG inhibits cardiomyocyte apoptosis in pressure overload-induced cardiac hypertrophy and protects cardiomyocytes from oxidative stress in rats.". Acta Pharmacologica Sinica. 28: 191–201. doi:10.1111/j.1745-7254.2007.00495.x. Retrieved 25 May 2016.