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Resenzitalizace leukemických a lymfomavých buněk k trailerem indukované apoptóze
Molinský, Jan ; Klener, Pavel (advisor) ; Hyršlová Vaculová, Alena (referee) ; Vyoral, Daniel (referee)
Apoptosis serves as a natural barrier to cancer development, and the resistance to apoptosis represents one of the key capabilities acquired during tumor development or progression. Impairment of the intrinsic apoptotic pathway exemplifies one of the established mechanisms of constitutive or acquired drug resistance. As most of the currently used cytotoxic drugs initiate tumor cell death by direct or indirect triggering of the intrinsic apoptotic pathway, impairment of the intrinsic pathway is associated with therapy failure. Targeting of the death receptors, however, enables induction of apoptosis even in the chemotherapy resistant cancer cells. TRAIL is a death ligand belonging to the TNFα superfamily that specifically kills tumor cells while sparing healthy tissues. Much enthusiasm has been generated for TRAIL as a highly promising targeted anti-cancer agent. However, many primary tumors have been shown to be TRAIL resistant. In attempt to overcome such an intrinsic TRAIL resistance a wide array of agents have been shown to sensitize tumor cells to TRAIL. Previous studies reported that roscovitine, a cyclin-dependent kinase inhibitor, sensitized various solid cancer cells to TRAIL. In this study we analyzed the sensitivity of diverse hematologic malignancies to TRAIL-induced apoptosis and measured the...
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Molecular mechanisms responsible for regulation of apoptosis in prostate cancer cells treated with TRAIL and chemotherapeutic drugs
Tománková, Silvie ; Hyršlová Vaculová, Alena (advisor) ; Špegárová, Jarmila (referee)
Prostate cancer is one of the most common cancer-related causes of death among men. Chemotherapy is mainly used for treatment of its later stages, accompanied by unpleasant side effects. So far, the treatment of advanced stages of prostate cancer has not been sufficient, and new more effective alternatives are needed. The application of the TRAIL cytokine, which induces apoptosis in tumor cell, but is not toxic to nonmalignant cells, seems to be a promissing approach. However, TRAIL-based therapy is often limited by the emerging cancer cell resistance. Overcoming the resistance can be achieved by combination therapy of TRAIL with effective sensitizers. Within this work, a combination of TRAIL with platinum-based chemotherapeutic drugs such as cisplatin or its novel derivative LA-12 was applied in order to facilitate the elimination of prostate cancer cells. In the experimental part of this work, using Western blot and flow cytometry analysis it was shown that TRAIL in combination with CDDP or LA-12 effectively enhanced apoptosis in three human prostate cancer cell lines. This effect was accompanied with increased activation/amount of several proapoptotic Bcl-2 family proteins, while no changes in the level of the receptors for TRAIL were observed. These results demonstrated that especially the combination...
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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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Mitochondria as a target for anti-cancer therapy by vitamin E analogues.
Kľučková, Katarína ; Neužil, Jiří (advisor) ; Hyršlová Vaculová, Alena (referee) ; Pecina, Petr (referee)
(EN) Based on the promising results concerning the anti-cancer properties of redox-silent analogue vitamin E α-tocopheryl succinate (α-TOS), we prepared its mitochondrially targeted derivative MitoVES by attaching the positively charged triphenylphosphonium (TPP+ ) tag to α-TOS molecule. We tested the hypothesis that 'sending' the drug directly to its cellular site of action, mitochondria, should enhance its anti-cancer properties, which would result in more effective anti-cancer agent while making it possible to reduce the effective concentration. We provide evidence that, indeed, MitoVES is a highly effective anti-cancer compound, superior to untargeted α-TOS both in vitro and in vivo. We show that MitoVES exerts its anti-cancer effects by interfering with complex II (CII) activity specifically at the ubiquinone binding site (Qp), where it blocks further electron transfer resulting in increased reactive oxygen species (ROS) production, which then leads to apoptosis induction via the intrinsic mitochondrial pathway, preferentially engaging the pro-apoptotic Bak protein causing mitochondrial membrane permeabilisation. We further show that mitochondrial targeting on the basis of higher mitochondrial membrane potential (ΔΨ) is important for MitoVES pro-apoptotic activity. This feature endows the...
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Resenzitalizace leukemických a lymfomavých buněk k trailerem indukované apoptóze
Molinský, Jan ; Klener, Pavel (advisor) ; Hyršlová Vaculová, Alena (referee) ; Vyoral, Daniel (referee)
Apoptosis serves as a natural barrier to cancer development, and the resistance to apoptosis represents one of the key capabilities acquired during tumor development or progression. Impairment of the intrinsic apoptotic pathway exemplifies one of the established mechanisms of constitutive or acquired drug resistance. As most of the currently used cytotoxic drugs initiate tumor cell death by direct or indirect triggering of the intrinsic apoptotic pathway, impairment of the intrinsic pathway is associated with therapy failure. Targeting of the death receptors, however, enables induction of apoptosis even in the chemotherapy resistant cancer cells. TRAIL is a death ligand belonging to the TNFα superfamily that specifically kills tumor cells while sparing healthy tissues. Much enthusiasm has been generated for TRAIL as a highly promising targeted anti-cancer agent. However, many primary tumors have been shown to be TRAIL resistant. In attempt to overcome such an intrinsic TRAIL resistance a wide array of agents have been shown to sensitize tumor cells to TRAIL. Previous studies reported that roscovitine, a cyclin-dependent kinase inhibitor, sensitized various solid cancer cells to TRAIL. In this study we analyzed the sensitivity of diverse hematologic malignancies to TRAIL-induced apoptosis and measured the...
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