Berberine has been used traditionally for its diverse pharmacological actions. It exhibits remarkable anticancer activities and is currently under clinical trials. In this study, we report that the anticancer activity of berberine could be partly due to its inhibitory actions on tubulin and microtubule assembly. Berberine inhibited the proliferation of HeLa cells with an IC of 18 μM and induced significant depolymerization of interphase and mitotic microtubules. At its IC, berberine exerted a moderate G2/M arrest and mitotic block as detected by fluorescence-activated cell sorting analysis and fluorescence microscopy, respectively. In a wound closure assay, berberine inhibited the migration of HeLa cells at concentrations lower than its IC, indicating its excellent potential as an anticancer agent. In vitro studies with tubulin isolated from goat brain indicated that berberine binds to tubulin at a single site with a K of 11 μM. Berberine inhibited the assembly of tubulin into microtubules and also disrupted the preformed microtubules polymerized in the presence of glutamate and paclitaxel. Competition experiments indicated that berberine could partially displace colchicine from its binding site. Results from fluorescence resonance energy transfer, computational docking, and molecular dynamics simulations suggest that berberine forms a stable complex with tubulin and binds at a novel site 24 Å from the colchicine site on the β-tubulin. Data obtained from synchronous fluorescence analysis of the tryptophan residues of tubulin and from the Fourier transform infrared spectroscopy studies revealed that binding of berberine alters the conformation of the tubulin heterodimer, which could be the molecular mechanism behind the depolymerizing effects on tubulin assembly.

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Humans have turned to natural products, obtained from plants, animals and aquatic life for treating diseases since time immemorial. Modern medicine is based on ancient wisdom transferred over generations. Drug development relies mainly on natural sources. Herbal medicines are making a comeback due to lower side effects, and positive results in the long term when compared to synthetic drugs. The current drug discovery process relies on identifying traditional medicines followed by Bioactivity-guided fractionation to isolate significant lead molecules. Plants have a history of long-term use by humans and hence it can be presumed that the bioactive compounds obtained from plants will have low human toxicity. There exists a huge potential for discovering new antitumor drug leads by screening natural products either in the form of crude extracts purified phytochemicals which have already been described in the literature. The fact that phytochemicals like paclitaxel, vinblastine, vincristine and camptothecin are being successfully used in clinical practice and several others like combretastatin and noscapine are in different stages of clinical trials implies the importance of plants in cancer chemotherapy.

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