Govender 2015 Abstract MiPschool Cape Town 2015

From Bioblast
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 Β΅M) for 24h followed by DXR treatment (3 Β΅M) 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 Β± 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 Β± 0.3733 % vs 38.88 Β± 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 Β± 0.084 fold vs 2.307Β± 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 Β± 3.797 % vs 64.43 Β± 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, MandalΓ  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.
Cookies help us deliver our services. By using our services, you agree to our use of cookies.