Tioconazole is one of the drugs used to treat topical mycotic
infections. It exhibited severe toxicity during systemic administration; however, the molecular mechanism behind the cytotoxic effect was not well established. We employed HeLa cells as a model to investigate the molecular mechanism of its toxicity and discovered that
tioconazole inhibited HeLa cell growth through mitotic block (37%). At the half-maximal inhibitory concentration (≈ 15 μM)
tioconazole apparently depolymerized microtubules and caused defects in chromosomal congression at the metaphase plate.
Tioconazole induced apoptosis and significantly hindered the migration of HeLa cells.
Tioconazole bound to goat brain
tubulin (K d, 28.3 ± 0.5 μM) and inhibited the assembly of microtubules in the in vitro assays. We report for the first time that
tioconazole binds near to the
colchicine site, based on the evidence from in vitro
tubulin competition experiment and computational analysis. The conformation of
tubulin dimer was found to be "curved" upon binding with
tioconazole in the MD simulation.
Tioconazole in combination with
vinblastine synergistically inhibited the growth of HeLa cells and augmented the percentage of mitotic block by synergistically inhibiting the assembly of microtubules. Our study indicates that the systemic adverse effects of
tioconazole are partly due to its effects on microtubules and cell cycle arrest. Since
tioconazole is well tolerated at the topical level, it could be developed as a topical
anticancer agent in combination with other systemic anticancer drugs.
GRAPHICAL ABSTRACT: The online version contains supplementary material available at 10.1007/s10616-021-00516-w.