Browsing by Author "Diogo, Vania"
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- Spindle Assembly Checkpoint as a Potential Target in Colorectal Cancer: Current Status and Future PerspectivesPublication . Diogo, Vania; Teixeira, Joana; Silva, Patrícia M.A.; Bousbaa, HassanColorectal cancer (CRC), one of the most common malignancies worldwide, is often diagnosed at an advanced stage, and resistance to chemotherapeutic and existing targeted therapy is a major obstacle to its successful treatment. New targets that offer alternative clinical options are therefore urgently needed. Recently, perturbation of the spindle assembly checkpoint (SAC), the surveillance mechanism that maintains anaphase inhibition until all chromosomes reach the metaphase plate, has been regarded as a promising target to fight cancer cells, either alone or in combination regimens. Consistent with this strategy, many cancers, including CRC, exhibit altered expression of SAC genes. In this article, we review our current knowledge on SAC activity status in CRC, and on current anti-CRC strategies and future therapeutic perspectives on the basis of SAC targeting experiments in vitro and in animal models. (C) 2016 Elsevier Inc. All rights reserved.
- Suppression of spindly delays mitotic exit and exacerbates cell death response of cancer cells treated with low doses of paclitaxelPublication . Silva, Patrícia M. A.; Ribeiro, Nilza; Lima, Raquel T.; Andrade, Claudia; Diogo, Vania; Teixeira, Joana; Florindo, C.; Tavares, Alvaro; Vasconcelos, M. Helena; Bousbaa, HassanMicrotubule-targeting agents (MTAs) are used extensively for the treatment of diverse types of cancer. They block cancer cells in mitosis through the activation of the spindle assembly checkpoint (SAC), the surveillance mechanism that ensures accurate chromosome segregation at the onset of anaphase. However, the cytotoxic activity of MTAs is limited by premature mitotic exit (mitotic slippage) due to SAC silencing. Here we have explored the dual role of the protein Spindly in chromosome attachments and SAC silencing to analyze the consequences of its depletion on the viability of tumor cells treated with clinically relevant doses of paclitaxel. As expected, siRNA-mediated Spindly suppression induced chromosome misalignment and accumulation of cells in mitosis. Remarkably, these cells were more sensitive to low-doses of paclitaxel. Sensitization was due to an increase in the length of mitotic arrest and high frequency of multinucleated cells, both correlated with an exacerbated post-mitotic cell death response as determined by cell fate profiling. Thus, by affecting both SAC silencing and chromosome attachment, Spindly targeting offers a double-edged sword that potentiates tumor cell killing by clinically relevant doses of paclitaxel, providing a rationale for combination chemotherapy against cancer. (C) 2017 Elsevier B.V. All rights reserved.