The Co-Administration of Paclitaxel with Novel Pyridine and Benzofuran Derivatives that Inhibit Tubulin Polymerisation: A Promising Anticancer Strategy.

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Background: Paclitaxel (PTX), a crucial microtubule-stabilising agent in cancer treatment, is limited by its adverse effects and hydrophobic nature, which necessitate the use of toxic solvents. This study proposes a novel approach combining PTX with new microtubule-destabilising compounds at low, safe doses that are ineffective when used individually. Objective: The aim was to evaluate the therapeutic efficacy of combining PTX with previously described pyridine (S1, S22) and benzofuran derivatives (13b, 14), which have demonstrated promising anticancer properties by inhibiting microtubule polymerisation. Methods: The PrestoBlue assay was used to determine the optimal concentrations of each compound, enabling synergistic interactions with a low dose of PTX in HeLa cervical cancer cells. The combined effects of the compounds and PTX on apoptosis, cell cycle distribution, and mitotic spindle formation were then evaluated. Results: The results showed that compounds 13b (1 µM), 14 (0.1 µM), S1 (2 µM), and S22 (2 µM) enhanced the proapoptotic and antimitotic effects of 1 nM PTX, which was ineffective alone. Notably, live-cell imaging revealed that the concurrent use of S1 and PTX produced effects similar to those of a higher PTX concentration (5 nM). Conclusions: These findings suggest that these compounds enhance the anticancer efficacy of low-dose PTX, potentially paving the way for more effective and safer cancer therapies.