Natural Bioactive as a Potential Therapeutic Approach for the Management of Cyclophosphamide-induced Cardiotoxicity

Cyclophosphamide (CP) is an extensively used anticancer drug, but its cardiotoxic manifestation is a major concern for its widespread clinical use. The observed cardiotoxic attributes have been reported at the therapeutic dose and often result into a high mortality rate and poor clinical outcome. Fall in the level of antioxidant enzymes catalase (CAT), reduced glutathione (GSH), superoxide dismutase (SOD) generation of reactive oxygen species (ROS), inflammatory cytokines nuclear factor kappa-light-chain enhancer of activated B cells (NF-kB), tumor necrosis factor-alpha (TNF-α), interleukin 1 beta (IL- 1β), apoptotic proteins (caspases) and direct damage to myocardial tissue (histological and ultrastructural damage) are some of the reported manifestations of cardiotoxicity. The observed clinical attributes of CP-induced cardiotoxicity are myocarditis, hemorrhage, thrombosis, myocardial infarction (MI), reduced ejection fraction, altered electrocardiogram (ECG) reading and heart failure. However, unlike Daxarazasone (an adjuvant to reduce doxorubicin-induced cardiotoxicity), no approved adjuvant is available to mitigate CPinduced cardiotoxicity. Thus, various natural bioactives have been explored for the possible cardioprotective effect against CP-induced cardiotoxicity. In the current manuscript, we have discussed the clinical and preclinical aspects of CP-induced cardiotoxicity, its clinically used combination with other anticancer drugs, and the available therapeutic regimen to mitigate this cardiotoxicity. Further, we discussed the limitations of available synthetic drugs used as an adjuvant and discussed various natural bioactive and their experimental details. This manuscript's overall goal is to throw light on CP-induced cardiotoxicity and summarize all the experimental data so that researchers working in this field may scientifically get up-to-date information in one place.