Anticancer Effect and Molecular Target Identification of Novel Anionophores in Lung Cancer
[eng] Oral and lung cancer are included in the most prevalent respiratory diseases, being the latter one of the main causes of mortality worldwide. Despite new advances in diagnosis and clinical care, success of conventional treatments is still limited since patients end up developing resistances an...
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| Tipo de recurso: | tesis doctoral |
| Estado: | Versión publicada |
| Fecha de publicación: | 2018 |
| País: | España |
| Institución: | Universidad de Barcelona |
| Repositorio: | Dipòsit Digital de la UB |
| OAI Identifier: | oai:diposit.ub.edu:2445/126829 |
| Acceso en línea: | https://hdl.handle.net/2445/126829 http://hdl.handle.net/10803/664165 |
| Access Level: | acceso abierto |
| Palabra clave: | Oncologia Càncer de boca Càncer de pulmó Mort cel·lular Oncology Oral cancer Lung cancer Cell death |
| Sumario: | [eng] Oral and lung cancer are included in the most prevalent respiratory diseases, being the latter one of the main causes of mortality worldwide. Despite new advances in diagnosis and clinical care, success of conventional treatments is still limited since patients end up developing resistances and presenting recurrences. Due to the therapeutic limitations to address these pathologies, it is necessary to identify new compounds, with different mechanisms of action and greater efficiency to overcome these neoplasms. Cancer cells acquire a series of characteristics during carcinogenesis, as a reversed pH gradient compared to normal cells, which favors cancer progression promoting proliferation and evasion of apoptosis. Recently, a new therapeutic strategy against cancer, which involves the modulation of intracellular pH has been proposed. Accordingly, our research group is focused on analyzing the potential of anion transporter compounds as new chemotherapeutic agents, since they possess the ability to selectively lower the intracellular pH. In particular, this doctoral thesis is focused on the anticancer effect characterization, at the cellular and molecular level, of novel anionophores, derived from natural compounds known as tambjamines. Firstly, the effect of the synthetic analogues on cell viability in oral and pulmonary cancer cell lines, as well as in cancer stem cells derived from patients’ tumors, has been determined, proving to be potent cytotoxic agents. Likewise, the implication of ion homeostasis disruption driven by these compounds has been studied at the cellular level. In this regard, it has been characterized how the compounds induce lysosomal alkalization and cause a massive vacuolization in the cytoplasm, which is consistent with mitochondrial swelling. These two phenomena led to the loss of function of both organelles. At the same time, the mechanisms of action linked to the osmotic imbalance caused by the compounds have been studied in detail. On one hand, it has been observed how these anionophores increase the activity of proteins related to cellular stress response, and how the apoptotic pathway is triggered, although this is not directly responsible for the death of the entire cell population. Likewise, an accumulation of autophagosomes, has been detected after treatment with these compounds, which might be related to the blockade of autophagy, consequence of the lysosomal failure after treatment with these compounds. Moreover, it has also been observed how the cells treated with these anionophores lose the integrity of the plasma membrane, indicating that the cytotoxic process culminates in necrosis in the vast majority of the cell population. Besides this, in this doctoral thesis, AKT protein has been identified as a potential molecular target of one of our compounds, using in silico docking experiments. In turn, it has been corroborated by surface plasmon resonance that the binding affinity between the selected tambjamine analogue and AKT is high, in the micromolar range. Likewise, a decrease in protein activity and in the total amount of AKT protein has been detected after treatment. Furthermore, the main signaling pathways involved in the cytotoxic process have been elucidated studying the modifications of miRNA expression patterns after the treatment with tambjamine, being the most affected PI3K / AKT, apoptosis and autophagy. Finally, to complete the preclinical studies, the toxicity and efficacy of these compounds in murine models of lung cancer have been evaluated in in vivo preliminary studies, showing a potent antitumor capacity in both ectopic and orthotopic models. Overall, these synthetic analogues of tambjamine may be considered a good tool to induce death in cancer cells through a new therapeutic strategy that modifies the intracellular pH and these compounds may become a good therapeutic option for apoptosis-resistant tumors. |
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