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Signalling pathways in pancreatic cancer and its treatment by targeting of mitochondria
Ezrová, Zuzana ; Neužil, Jiří (advisor) ; Masařík, Michal (referee) ; Divoký, Vladimír (referee)
Pancreatic cancer is one of the deadliest types of malignant diseases. Asymptomatic early tumour stages, tumour heterogeneity, cancer cell plasticity and unusually dense pancreatic stroma are responsible for the poor prognosis attributed to late diagnosis and therapy resistance. Therefore, targeting of a pivotal element common for any cell type within the tumour, e.g. mitochondria, may bring significant improvement. In this work, we demonstrate mitochondrial targeting of metformin, an anti-diabetic drug associated with reduced risk of developing pancreatic cancer, substantially increases accumulation of the compound in mitochondria. In consequence, we show that mitochondrially targeted metformin, MitoMet, eliminates pancreatic cancer cells in more than 1000-fold lower concentration than used for its parental compound. Following interaction with respiratory complex I (CI), MitoMet inhibits mitochondrial respiration, activates AMP-activated protein kinase pathway and causes depolarization of mitochondrial membrane potential in pancreatic cancer cells. Moreover, MitoMet induces cell cycle arrest and apoptosis, which is partially mediated via increased level of reactive oxygen species (ROS), and suppresses pancreatic tumour growth in vivo. Interestingly, SMAD4-deficient pancreatic cancer cells manifest...
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Molecular mechanisms of cell death induction in pancreatic cancer cells
Ezrová, Zuzana ; Neužil, Jiří (advisor) ; Hyršlová Vaculová, Alena (referee)
Pancreatic adenocarcinoma is one of the most challenging types of tumours to treat; furthermore, standard therapies used so far turn out to be highly inadequate in its treatment. There has been no significant progress in the introduction of new therapeutic approaches to date, and so this disease remains one of the most common causes of death from cancer. Currently, many scientific papers refer to the potential use of metformin, the substance of the biguanide class most commonly used to treat diabetes mellitus type 2. Metformin, according to retrospective studies, reduces the risk of pancreatic cancer in diabetics, possibly by interacting with the complex I of electron transport chain. However, laboratory research registered neoplastic activity of this compound at super-physiological concentrations that are very difficult to achieve in patients. Due to the growing body of evidence of indispensability of functional mitochondria in the initiation and development of malignant neoplasms, we have, in collaboration with other researchers, modified metformin to strengthen its accumulation in mitochondria. We expected that mitochondrially targeted metformin, norMitoMet, will be considerably more efficiency in comparison with the parental compound. The main focus of this study is to shed light on the...
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Genes participating in response to Leishmania major revealed by targeted mutation.
Ezrová, Zuzana ; Lipoldová, Marie (advisor) ; Krulová, Magdaléna (referee)
Leishmania major is an intracellular parasite which often successfully multiplies and disseminates in a body of the host thanks to strategies that help it to escape the components of immune system of the host organism. Thus, the parasites evoke an impairment of regulatory pathways that in physiological conditions lead to an expression of genes involved in a response to L. major and its efficient elimination. Gene targeted deletion, also called gene knock-out, can result in phenotypic alteration and associated enhanced susceptibility or resistance of the host. Although such detected genes do not have to signify their variability in population and hence they may not be responsible for the worsened outcome of leishmaniasis of some people necessarily, studies in which they are analysed and general knowledge being also a subject of this thesis help us together with techniques of forward genetics to reveal the biochemical pathways during the infection and their elements that influence the outcome of the disease and might be useful for researches of new medicine drugs or gene therapy.
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