Development of 2D optical array sensors based on the combined utilization of multiple luminescent quantum dots immobilized onto solid supports

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A Pyranoxanthone as a potent antimitotic and sensitizer of cancer cells to low doses of Paclitaxel

Publication . França, Fábio; Silva, Patrícia M. A.; Soares, José X.; Henriques, Ana C.; Loureiro, Daniela R. P.; Azevedo, Carlos M. G.; Afonso, Carlos M. M.; Bousbaa, Hassan

Microtubule-targeting agents (MTAs) remain a gold standard for the treatment of several cancer types. By interfering with microtubules dynamic, MTAs induce a mitotic arrest followed by cell death. This antimitotic activity of MTAs is dependent on the spindle assembly checkpoint (SAC), which monitors the integrity of the mitotic spindle and proper chromosome attachments to microtubules in order to ensure accurate chromosome segregation and timely anaphase onset. However, the cytotoxic activity of MTAs is restrained by drug resistance and/or toxicities, and had motivated the search for new compounds and/or alternative therapeutic strategies. Here, we describe the synthesis and mechanism of action of the xanthone derivative pyranoxanthone 2 that exhibits a potent anti-growth activity against cancer cells. We found that cancer cells treated with the pyranoxanthone 2 exhibited persistent defects in chromosome congression during mitosis that were not corrected over time, which induced a prolonged SAC-dependent mitotic arrest followed by massive apoptosis. Importantly, pyranoxanthone 2 was able to potentiate apoptosis of cancer cells treated with nanomolar concentrations of paclitaxel. Our data identified the potential of the pyranoxanthone 2 as a new potent antimitotic with promising antitumor potential, either alone or in combination regimens.

2020Journal article

Open access

Investigating the antitumoral activity and mechanism of action of a xanthone derivative

Publication . Silva, Fábio França Vieira e; Tavares, Álvaro; Bousbaa, Hassan; Silva, Patrícia Manuela Areias da

Chapter I refers to the introduction, and has the role of providing an initial overview of the issues addressed directly or indirectly in the rest of the study. Initially, an overview of the cell cycle, its regulation and control is given. In the sequence, a greater emphasis is given to mitosis, which is described in detail from its cascade of events to the molecular machinery of the mitotic spindle. Still at this stage, the dynamics that occur between kinetochore-microtubules, correlated errors and their due corrections are described. Next, we provide an overview of the Spindle Assembly Checkpoint (SAC), dissecting the functions triggered by this mechanism, as well as the proteins involved in this important cellular control mechanism. Following, an introduction was given about drugs that use the targeting of mitosis for cancer therapy, namely through microtubules, providing an overview of current approaches, their limitations and future directions. Finally, a correlation was made between xanthones and cancer, demonstrating how this class of compounds (as well as their derivatives) is already used as a starting point in the development of new anticancer drugs. Chapter II concerns what motivated the project, as well as its specific objectives. Chapter III refers to the materials and methods used throughout the study, so that it was possible to dissect the mechanism of action of the compound. Chapter IV will demonstrate the results about the compound's mechanism of action, through: in vitro characterization of the compound's antimitotic activity, identification of the underlying mechanism of action and evaluation of the combined treatment of PX2 with paclitaxel in promoting cell death of tumoral cells. Chapter V provides a discussion, correlating previous studies and the present study. Chapter VI provides general conclusions about the mechanism of action of PX2 and the prospects for future research. Chapter VII contains a list of all references cited in the course of the thesis.

2020-12-18Master thesis

Open access