Phloretin ameliorates arsenic trioxide induced mitochondrial dysfunction in H9c2 cardiomyoblasts mediated via alterations in membrane permeability and ETC complexes.
Arsenic trioxide (ATO), though a very effective drug for the treatment of acute promyelocytic leukemia, leads to cardiotoxicity. As mitochondria are the center of attention of cardiac cell׳s general metabolic status, it is primarily important to see the interaction of ATO with mitochondria. Studies related exclusively to the alterations in mitochondria and its associated functions caused by ATO are very limited. The present investigation aims to explore the effect of ATO on various components of electron transport chain, oxygen consumption, ATP production, mitochondrial superoxide generation, transmembrane potential, permeability pore opening, calcium homeostasis and apoptosis. Attempts were also made to see the efficacy of phloretin, a potent antioxidant flavonoid found majorly in apple peel on cardiotoxicity. The H9c2 cells exposed to ATO (5µM) exhibited increased oxidative stress with reduced innate antioxidant status, mitochondrial dysfunctions and apoptosis. It increased the intracellular calcium content, caused alterations in the activity of transcription factor Nrf2, xanthine oxidase, aconitase and caspase 3 compared to the control group. Phloretin at 2.5 and 5µM concentrations were able to protect the cells from ATO toxicity via protecting mitochondria through its antioxidant potential. The present investigation based on mitochondria reveals the probability of cardioprotective potential of phloretin for the cancer patients on ATO chemotherapy.
Agroprocessing and Natural Products Division, Council for Scientific and Industrial Research - National Institute for Interdisciplinary Science and Technology (CSIR - NIIST), Thiruvananthapuram, Kerala 695019, India.
Vadavanath Prabhakaran
VP
Vineetha
Agroprocessing and Natural Products Division, Council for Scientific and Industrial Research - National Institute for Interdisciplinary Science and Technology (CSIR - NIIST), Thiruvananthapuram, Kerala 695019, India.
Rema Sreenivasan
RS
Soumya
Agroprocessing and Natural Products Division, Council for Scientific and Industrial Research - National Institute for Interdisciplinary Science and Technology (CSIR - NIIST), Thiruvananthapuram, Kerala 695019, India. Electronic address: raghukgopal2009@gmail.com.
Kozhiparambil Gopalan
KG
Raghu
D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D000077237:Arsenic Trioxide; D001152:Arsenicals / Q000009:adverse effects*; D002118:Calcium / Q000378:metabolism; D002463:Cell Membrane Permeability / Q000187:drug effects*; D002478:Cells, Cultured; D045222:Electron Transport Chain Complex Proteins / Q000378:metabolism*; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D008928:Mitochondria / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology*; D032446:Myoblasts / Q000187:drug effects / Q000473:pathology; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000473:pathology; D018384:Oxidative Stress / Q000187:drug effects*; D010087:Oxides / Q000009:adverse effects*; D010101:Oxygen Consumption / Q000187:drug effects; D010693:Phloretin / Q000494:pharmacology*; D051381:Rats; D017382:Reactive Oxygen Species / Q000378:metabolism; D013481:Superoxides / Q000378:metabolism
D000975:Antioxidants; D001152:Arsenicals; D045222:Electron Transport Chain Complex Proteins; D010087:Oxides; D017382:Reactive Oxygen Species; D013481:Superoxides; D000255:Adenosine Triphosphate; D010693:Phloretin; D000077237:Arsenic Trioxide; D002118:Calcium
Arsenic trioxide; Electron transport chain; H9c2 cells; Mitochondrial swelling; Oxygen consumption; Phloretin