Abstract
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.
Highlights
Cancer remains a major cause of death worldwide and new cases resulting from an aging population are expected to increase [1]
We unveiled the mechanism of the cytotoxic activity of the xanthone derivative pyranoxanthone 2
We demonstrated that pyranoxanthone 2 disturbs the mitotic spindle, which lead to unstable kinetochore-microtubules attachments and chromosome misalignment that activate spindle assembly checkpoint (SAC), thereby leading to prolonged mitotic arrest and, subsequently, cell death, in NCI-H460 human lung carcinoma
Summary
Cancer remains a major cause of death worldwide and new cases resulting from an aging population are expected to increase [1]. Even considering only the antitumor activity, the biological activity of xanthones depends on the position and types of substituents on the scaffold providing a broad spectrum of activity [19], namely the interference with various mechanisms of the tumor cell: blocking the cell cycle, preventing the proliferation of the tumor cell, directing apoptosis, triggering DNA repair, functioning as an anti-inflammatory agent, and preventing the recruitment of cells necessary in angiogenesis and, metastasis [20] This propelled us to design and produce synthetic pyranoxanthone derivatives, which by overcoming the biosynthetic pathways impositions allows the merging of xanthone (Figure 1, highlighted with yellow and green) and benzopyran (Figure 1, highlighted with green and blue) scaffolds [21,22]. Our data highlight the potential of the pyranoxanthone 2 as a new and promising antimitotic with effective antitumor activity in vitro
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