Loss of endogenous estrogen increases cardiac toxicity by doxorubicin

Lee, Young Ho; Lee, Sang R; Kwon, Sun Woo; Lee, Seung yeon; Park, Bae kuen; Hong, Eui Ju

Abstract

Breast cancer is of enormous concern worldwide and linked with age, sex, hormonal factors, and family history. The treatment of early breast cancer includes treating the disease locally with surgery, radiation therapy, or both and treating microscopic systemic disease with either one or a combination of chemotherapy, endocrine therapy, or biologic therapy. Doxorubicin is a well-known anthracycline antibiotic and antineoplastic drug usually administered to breast cancer patients. However, there have been some reports suggesting that doxorubicin causes side effects such as cardiotoxicity. Furthermore, breast cancer patients on doxorubicin treatment are commonly prescribed steroid suppression therapy. In addition, it has been previously reported that lack of estrogen elevates cardiotoxicity. In this study, we evaluated whether the steroid suppression therapy might influence the cardiotoxicity of doxorubicin. We hypothesized that the presence of a steroid hormone, particularly estrogen, is closely related to doxorubicin action. To investigate the effect of estrogen, mice were divided into four groups: control group, doxorubicin-treated group, ovariectomized group, and ovariectomized plus doxorubicin-treated group. We observed upregulation of inflammatory cytokine gene and downregulation of apoptotic genes in the groups treated with doxorubicin, particularly in the ovariectomized plus doxorubicin-treated group. This suggests that administration of doxorubicin under a non-steroid condition can excessively damage the heart. In summary, combination treatment of hormonal and doxorubicin therapy for breast or many different types of cancer patients must be prescribed with requisite precautions.