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Molecular bases of sensitivity to electron transport chain inhibition-induced cell death
Blecha, Jan
1 Abstract in English Mitochondrial electron transport chain (ETC) targeting shows a great promise in cancer therapy. However, why modern ETC-targeted compounds are tolerated on the organismal level and what are the molecular reasons for this tolerance remains unclear. Most somatic cells are in a non-proliferative state, and features associated with the ETC in quiescence might therefore contribute to specificity. Thus, we investigated the ETC status and the role of two major consequences of ETC blockade, reactive oxygen species (ROS) generation and inhibition of ATP production, in cell death induction in breast cancer cells and in proliferating and quiescent non-transformed cells. First, we characterised the effect of a newly developed ETC inhibitor mitochondria- targeted tamoxifen (MitoTam) in in vitro and in vivo tumour models of breast cancer with varying status of the Her2 oncogene. We document that Her2high cells and tumours have increased assembly of respiratory supercomplexes (SCs) and increased complex I-driven respiration in vitro and in vivo. They are also highly sensitive to MitoTam. Unlike the parental compound tamoxifen, MitoTam efficiently suppressed experimental Her2high tumours without systemic toxicity. Mechanistically, MitoTam inhibits complex I- driven respiration and disrupts respiratory...
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Molecular bases of sensitivity to electron transport chain inhibition-induced cell death
Blecha, Jan
1 Abstract in English Mitochondrial electron transport chain (ETC) targeting shows a great promise in cancer therapy. However, why modern ETC-targeted compounds are tolerated on the organismal level and what are the molecular reasons for this tolerance remains unclear. Most somatic cells are in a non-proliferative state, and features associated with the ETC in quiescence might therefore contribute to specificity. Thus, we investigated the ETC status and the role of two major consequences of ETC blockade, reactive oxygen species (ROS) generation and inhibition of ATP production, in cell death induction in breast cancer cells and in proliferating and quiescent non-transformed cells. First, we characterised the effect of a newly developed ETC inhibitor mitochondria- targeted tamoxifen (MitoTam) in in vitro and in vivo tumour models of breast cancer with varying status of the Her2 oncogene. We document that Her2high cells and tumours have increased assembly of respiratory supercomplexes (SCs) and increased complex I-driven respiration in vitro and in vivo. They are also highly sensitive to MitoTam. Unlike the parental compound tamoxifen, MitoTam efficiently suppressed experimental Her2high tumours without systemic toxicity. Mechanistically, MitoTam inhibits complex I- driven respiration and disrupts respiratory...
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Molecular bases of sensitivity to electron transport chain inhibition-induced cell death
Blecha, Jan ; Rohlena, Jakub (advisor) ; Brábek, Jan (referee) ; Pecinová, Alena (referee)
1 Abstract in English Mitochondrial electron transport chain (ETC) targeting shows a great promise in cancer therapy. However, why modern ETC-targeted compounds are tolerated on the organismal level and what are the molecular reasons for this tolerance remains unclear. Most somatic cells are in a non-proliferative state, and features associated with the ETC in quiescence might therefore contribute to specificity. Thus, we investigated the ETC status and the role of two major consequences of ETC blockade, reactive oxygen species (ROS) generation and inhibition of ATP production, in cell death induction in breast cancer cells and in proliferating and quiescent non-transformed cells. First, we characterised the effect of a newly developed ETC inhibitor mitochondria- targeted tamoxifen (MitoTam) in in vitro and in vivo tumour models of breast cancer with varying status of the Her2 oncogene. We document that Her2high cells and tumours have increased assembly of respiratory supercomplexes (SCs) and increased complex I-driven respiration in vitro and in vivo. They are also highly sensitive to MitoTam. Unlike the parental compound tamoxifen, MitoTam efficiently suppressed experimental Her2high tumours without systemic toxicity. Mechanistically, MitoTam inhibits complex I- driven respiration and disrupts respiratory...
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Reactive oxygen species and their role in myocard injury
Selingerová, Josefína ; Kalous, Martin (advisor) ; Rauchová, Hana (referee)
Cardiac tissue is very sensitive to oxygen deprivation. Ischemia and subsequent reperfusion are the source of metabolic and structural changes. They lead to irreversible tissue damage and cell death. Under this conditions the increased production of reactive oxygen species (ROS) is crucial. ROS are highly reactive molecules, which contains at least one unpaired electron. They are formed in organism as a natural by-products of aerobic metabolism. Under physiological conditions mitochondria protect cells against ROS trough antioxidants sweeper systems and ATP synthase inhibitor. However, under pathological conditions mitochondria are one of the largest sources of ROS and they are responsible for initiation of cell death. This thesis discusses the changes in cells during the ischemia and following reperfusion. How is ion homeostasis and ATP concentration affected and why the activities of individual complexes of electron-transport chain are decreased.
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