Govender 2015 Abstract MiPschool Cape Town 2015

Mitochondrial catastrophe during doxorubicin-induced cardiotoxicity: The protective role of melatonin.

Link:

Govender J, Loos B, Engelbrecht AM, Francois van der Westhuizen FH (2015)

Event: MiPschool Cape Town 2015

Anthracyclines, such as doxorubicin (DXR), are among the most valuable treatments for various cancers, but their clinical use is limited due to detrimental side-effects such as cardiotoxicity. DXR-induced cardiotoxicity is emerging as a critical issue among cancer survivors and is an area of much significance to the field of cardio-oncology. The abundance of mitochondria in cardiomyocytes closely links mitochondrial bioenergetics with myocardial function and viability [1]. It has been demonstrated that DXR specifically targets mitochondria and increases the generation of reactive oxygen species (ROS), decreases adenosine triphosphate (ATP) production and modulates mitochondrial sirtuin activity; thus, mitochondrial dysfunction has recently been recognized as a pivotal element in the development of DXR-induced cardiotoxicity [2]. In light of this scenario, both endogenously produced and exogenously administered melatonin during or prior chemotherapy shows great promise in this therapeutic avenue as demonstrated in various studies [3]. MLT is a potent anti-oxidant, is non-toxic, is dually oncostatic and cardio-protective, and has been shown to influence mitochondrial homeostasis and function [3,4]. Although a number of studies support the mitochondrial protective role of MLT, the exact mechanisms by which MLT confers mitochondrial protection in the context of DXR-induced cardiotoxicity remain to be elucidated. This study evaluated the role of MLT on mitochondrial function, mitochondrial dynamics and cell death during DXR-induced cardiotoxicity. H9C2 rat cardiac myoblasts were pre-treated with MLT (10 µM) for 24h followed by DXR treatment (3 µM) for 24h. Following treatment, mitochondrial reductive capacity and apoptotic cell death were assessed. Mitochondrial bioenergetic parameters was analysed using the XF96 analyser (extracellular flux). These results indicate a significant decrease in mitochondrial reductive capacity in response to DXR treatment versus the control (38.88 ± 0.3435 % vs 100%, p< 0.0001). Cells pre-treated with MLT followed by DXR treatment showed a significant increase in mitochondrial reductive capacity versus the DXR treated group only (97.45 ± 0.3733 % vs 38.88 ± 0.3435 %, p< 0.0001). Furthermore, a significant decrease in caspase 3/7 activity was detected when cells were pre-treated with MLT followed by DXR treatment versus the DXR treated group only (1.649 ± 0.084 fold vs 2.307± 0.1035 fold, p< 0.001). ATP turnover was significantly increased when cells were pre-treated with MLT followed by DXR treatment versus the DXR treated group only (48.39 ± 3.797 % vs 64.43 ± 2.670 %, p< 0.001). These results strongly indicate that pre-treatment with MLT confers a mitochondrial cardioprotective effect during DXR-induced cardiotoxicity by significantly increasing cardiac myocytes viability and influencing mitochondrial bioenergetics.

Labels: MiParea: mt-Biogenesis;mt-density, mt-Medicine, Patients  Pathology: Cancer  Stress:Cell death, Oxidative stress;RONS  Organism: Human, Rat  Tissue;cell: Heart 

Affiliations

1-Dept Physiol Sci, Stellenbosch Univ, South Africa. - [email protected]

2-Dept Biochem, North-West Univ, South Africa

References

1. Gottlieb RA and Gustafsson AB (2011) Mitochondrial turnover in the heart. Biochim Biophys Acta 1813:1295-1301.
2. Tokarska-Schlattner M, Zaugg M, Zuppinger C, Wallimann T, Schlattner U (2006) New insights into doxorubicin-induced cardiotoxicity: the critical role of cellular energetics. J Mol Cell Cardiol 41:389-405.
3. Reiter RJ (1991) Melatonin: the chemical expression of darkness. Mol Cell Endocrinol 79:C153-8.
4. Lissoni P, Barni S, Mandalà M, Ardizzoia A, Paolorossi F, Vaghi M, Longarini R, Malugani F, Tancini G (1999) Decreased toxicity and increased efficacy of cancer chemotherapy using the pineal hormone melatonin in metastatic solid tumour patients with poor clinical status. Eur J Cancer 35:1688-92.