Cardioprotective Effect of Melatonin Versus Vitamin D in Breast Cancer Patients Receiving Doxorubicin

Doxorubicin is one of the most potent chemotherapeutic agents and is widely used for the treatment of various cancers and hematological malignancies . Although Doxorubicin has a potential beneficial effect in cancer treatment, its dose-dependent cardio toxicity is considered a major challenge.

Doxorubicin is known to generate free radicals either by redox cycling between a semiquinone form and a quinone form or by forming a Doxorubicin-Fe3+ complex . In both pathways, molecular oxygen is reduced to superoxide ion , which is converted to other forms of reactive oxygen species such as hydrogen peroxide and hydroxyl radical . These free radicals could then cause membrane and macromolecule damage, both of which lead to injury to the heart, an organ that has a relatively low level of antioxidant enzymes such as superoxide dismutase and catalase .

Furthermore, it was revealed that Doxorubicin may enhance the death of cardiomyocytes by affecting the tumor necrosis factor signaling pathway via increasing the expression and levels of inflammatory genes interleukin and interleukin -6 .

To alleviate DOX-induced toxicity, researchers have tested a number of strategies, including the administration of antioxidants and/or antiapoptotic agents, in both in vitro and in vivo models of Doxorubicin induced cytotoxicity, but most of these trials have failed to translate into clinical benefits . As a result, there are no effective approaches for alleviating Doxorubicin induced cytotoxicity despite intensive research over recent decades .

Melatonin is a natural hormone that is primarily secreted by the pineal gland and functions as a major regulator of circadian rhythms in humans . Melatonin also plays a variety of biological roles as a modulator of mood, sexual behavior and sleep; low levels or a deficiency of melatonin are also associated with Parkinson's disease, Alzheimer's disease, epilepsy, ischemic injury, diabetes, and even cancer .

Melatonin has emerged as a promising adjuvant that protects against doxorubicin-induced cytotoxicity, as highlighted by various studies and clinical trials that have demonstrated cardioprotective effects against several chemotherapeutic agents . Moreover, melatonin exhibits low toxicity and easily enters cells owing to its good solubility in both aqueous and organic phases and its highly lipophilic properties . Vitamin D plays an important role in the regulation of body function including the cardiovascular system .

Vitamin D deficiency results in the decrease of active calcitriol leading to inhibition of proliferation of cardiomyocytes and vascular smooth muscles .

This study aims to assess the cardioprotective effect of melatonin and vitamin D in breast cancer patients who receive doxorubicin.

Inclusion criteria

• Age from 18 to 65 years old.
• Gender: female.
• Positive breast cancer women who are scheduled to receive Doxorubicin.
• Have a good performance status according to the eastern cooperative oncology group with a score of 0-2.
• Normal baseline Echocardiography with left ventricular ejection fraction ≥ 50%.
• Normal renal and liver function tests.

Exclusion criteria

• Pregnant or breastfeeding women.
• Women with HER-2 positive of breast cancer.
• Formerly treated with Doxorubicin.
• Patients with a known hypersensitivity to any of the used drugs.
• On other concomitant vitamins or food supplements.
• Valvular heart disease, coronary artery disease, history of congestive heart failure or cardiomyopathy.
• Impaired Left ventricular systolic function in which the Left Ventricular Ejection Fraction < 50%.