A Pyranoxanthone as a Potent Antimitotic and Sensitizer of Cancer Cells to Low Doses of Paclitaxel
Fábio França,
Patrícia M. A. Silva,
José X. Soares,
Ana C. Henriques,
Daniela R. P. Loureiro,
Carlos M. G. Azevedo,
Carlos M. M. Afonso,
Hassan Bousbaa
Affiliations
Fábio França
CESPU, Institute of Research and Advanced Training in Health Sciences and Technologies (IINFACTS), University Institute of Health Sciences (IUCS), Rua Central de Gandra, 1317, 4585-322 Gandra, Portugal
Patrícia M. A. Silva
CESPU, Institute of Research and Advanced Training in Health Sciences and Technologies (IINFACTS), University Institute of Health Sciences (IUCS), Rua Central de Gandra, 1317, 4585-322 Gandra, Portugal
José X. Soares
LAQV-REQUIMTE, Department of Chemical Sciences, Laboratory of Applied Chemistry, Faculty of Pharmacy, University of Porto, Rua de Jorge Viterbo Ferreira, 228, 4050-313 Porto, Portugal
Ana C. Henriques
CESPU, Institute of Research and Advanced Training in Health Sciences and Technologies (IINFACTS), University Institute of Health Sciences (IUCS), Rua Central de Gandra, 1317, 4585-322 Gandra, Portugal
Daniela R. P. Loureiro
Interdisciplinary Center of Marine and Environmental Investigation (CIIMAR/CIMAR), Edifício do Terminal de Cruzeiros do Porto de Leixões, Av. General Norton de Matos s/n, 4050-208 Matosinhos, Portugal
Carlos M. G. Azevedo
Department of Chemical Sciences, Laboratory of Organic and Pharmaceutical Chemistry, Faculty of Pharmacy, University of Porto, 4050-313 Porto, Portugal
Carlos M. M. Afonso
Interdisciplinary Center of Marine and Environmental Investigation (CIIMAR/CIMAR), Edifício do Terminal de Cruzeiros do Porto de Leixões, Av. General Norton de Matos s/n, 4050-208 Matosinhos, Portugal
Hassan Bousbaa
CESPU, Institute of Research and Advanced Training in Health Sciences and Technologies (IINFACTS), University Institute of Health Sciences (IUCS), Rua Central de Gandra, 1317, 4585-322 Gandra, Portugal
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.
