Browsing by Author "Chabaesele, Itumeleng"

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    Does cardioprotection by autophagy go beyond acute cardiotoxicity?
    (Stellenbosch : Stellenbosch University, 2016-03) Chabaesele, Itumeleng; Sishi, Balindiwe J. N.; Stellenbosch University. Faculty of Science. Dept. of Physiological Sciences.
    ENGLISH ABSTRACT: Introduction and Aim The discovery of Doxorubicin (DOX) in the 1960s has drastically improved the survival rates of cancer patients; however, its success is limited by dose-dependent cardiotoxicity. While much of the literature has focused on acute cardiotoxicity which is generally reversible, chronic cardiotoxicity is irreversible and poses a serious threat since it can lead to congestive heart failure. The mechanisms that contribute to cardiotoxicity are still a matter of controversy; however, oxidative stress-induced myocardial damage and apoptosis are thought to be the major role players. One of the best understood and most widely studied processes is autophagy, an evolutionary conserved pathway of intracellular degradation. Although it has been attributed to various cardiac disorders, an increasing body of evidence corroborates the notion that autophagy may serve as a probable therapeutic target by providing cardioprotection in different contexts. Materials Autophagy was induced in H9c2 cardiomyoblasts by rapamycin treatment, starvation and siRNA (mTOR). This process was also inhibited by bafilomycin A1 treatment. Chronic DOX cytotoxicity was induced by treating cells daily with 0.2 μM DOX for 120 hrs. In an effort to determine whether autophagy upregulation or downregulation was beneficial, cell viability, apoptosis, oxidative stress and mitochondrial membrane function were assessed by utilizing various assays, western blotting, fluorescence microscopy as well as flow cytometry. Results and Conclusion Autophagy stimulation via siRNA (mTOR) and autophagy inhibition with bafilomycin did not decrease the detrimental effects associated with long-term DOX cytotoxicity. These effects were instead aggravated and became progressively worse. However, autophagy upregulation through rapamycin or starvation proved beneficial in this context as the amount of DOX that normally accumulates in the cells was reduced, and mitochondrial function and damage substantially improved. These observations also lead to improved cell survival. Therefore, based on the above results, autophagy induction in this context may be used as a plausible adjuvant treatment strategy for the mitigation of DOX-induced cardiac damage.