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Zerumbone, a cyclic sesquiterpene, exerts antimitotic activity in HeLa cells through tubulin binding and exhibits synergistic activity with vinblastine and paclitaxel.

ABSTRACT: OBJECTIVES:The aim of this study was to elucidate the antimitotic mechanism of zerumbone and to investigate its effect on the HeLa cells in combination with other mitotic blockers. MATERIALS AND METHODS:HeLa cells and fluorescence microscopy were used to analyse the effect of zerumbone on cancer cell lines. Cellular internalization of zerumbone was investigated using FITC-labelled zerumbone. The interaction of zerumbone with tubulin was characterized using fluorescence spectroscopy. The Chou and Talalay equation was used to calculate the combination index. RESULTS:Zerumbone selectively inhibited the proliferation of HeLa cells with an IC50 of 14.2 ± 0.5 ?mol/L through enhanced cellular uptake compared to the normal cell line L929. It induced a strong mitotic block with cells exhibiting bipolar spindles at the IC50 and monopolar spindles at 30 ?mol/L. Docking analysis indicated that tubulin is the principal target of zerumbone. In vitro studies indicated that it bound to goat brain tubulin with a Kd of 4 ?mol/L and disrupted the assembly of tubulin into microtubules. Zerumbone and colchicine had partially overlapping binding site on tubulin. Zerumbone synergistically enhanced the anti-proliferative activity of vinblastine and paclitaxel through augmented mitotic block. CONCLUSION:Our data suggest that disruption of microtubule assembly dynamics is one of the mechanisms of the anti-cancer activity of zerumbone and it can be used in combination therapy targeting cell division.

SUBMITTER: Ashraf SM

PROVIDER: S-EPMC6496756 | biostudies-literature | 2019 Mar

REPOSITORIES: biostudies-literature

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Zerumbone, a cyclic sesquiterpene, exerts antimitotic activity in HeLa cells through tubulin binding and exhibits synergistic activity with vinblastine and paclitaxel.

Ashraf Shabeeba M SM Sebastian Jomon J Rathinasamy Krishnan K

Cell proliferation 20181207 2

<h4>Objectives</h4>The aim of this study was to elucidate the antimitotic mechanism of zerumbone and to investigate its effect on the HeLa cells in combination with other mitotic blockers.<h4>Materials and methods</h4>HeLa cells and fluorescence microscopy were used to analyse the effect of zerumbone on cancer cell lines. Cellular internalization of zerumbone was investigated using FITC-labelled zerumbone. The interaction of zerumbone with tubulin was characterized using fluorescence spectroscop ...[more]

PMID: 30525278

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Project description:Kaempferia parviflora (KP) has been traditionally used as a folk remedy to treat several diseases including cancer, and several studies have reported cytotoxic activities of extracts of KP against a number of different cancer cell lines. However, many aspects of the molecular mechanism of action of KP remain unclear. In particular, the ability of KP to regulate cancer cell growth and survival signaling is still largely unexplored. The current study aimed to investigate the effects of KP on cell viability, cell migration, cell invasion, cell apoptosis, and on signaling pathways related to growth and survival of cervical cancer cells, HeLa. We discovered that KP reduced HeLa cell viability in a concentration-dependent manner. The potent cytotoxicity of KP against HeLa cells was associated with a dose-dependent induction of apoptotic cell death as determined by flow cytometry and observation of nuclear fragmentation. Moreover, KP-induced cell apoptosis was likely to be mediated through the intrinsic apoptosis pathway since caspase 9 and caspase 7, but not BID, were shown to be activated after KP exposure. Based on the observation that KP induced apoptosis in HeLa cell, we further investigated the effects of KP at non-cytotoxic concentrations on suppressing signal transduction pathways relevant to cell growth and survival. We found that KP suppressed the MAPK and PI3K/AKT signaling pathways in cells activated with EGF, as observed by a significant decrease in phosphorylation of ERK1/2, Elk1, PI3K, and AKT. The data suggest that KP interferes with the growth and survival of HeLa cells. Consistent with the inhibitory effect on EGF-stimulated signaling, KP potently suppressed the migration of HeLa cells. Concomitantly, KP was demonstrated to markedly inhibit HeLa cell invasion. The ability of KP in suppressing the migration and invasion of HeLa cells was associated with the suppression of matrix metalloproteinase-2 production. These data strongly suggest that KP may slow tumor progression and metastasis in patients with cervical cancer. Taken together, the present report provides accumulated evidence revealing the potent anti-cancer activities of Kaempferia parviflora against cervical cancer HeLa cells, and suggests its potential use as an alternative way for cervical cancer prevention and therapy.

Project description:Vinblastine (VLB) is an antimitotic drug that binds to the vinca site of tubulin. The molecule possesses a high molecular weight and a complex chemical structure with many possibilities of metabolization. Despite advances in drug discovery research in reducing drug toxicity, the cause and mechanism of VLB-induced adverse drug reactions (ADRs) remains poorly understood. VLB is metabolized to at least 35 known metabolites, which have been identified and collected in this present work. This study also explores how VLB metabolites affect nausea-associated receptors such as muscarinic, dopaminergic, and histaminic. The metabolites have stronger binding interactions than acetylcholine (ACh) for muscarinic M1, M4, and M5 receptors and demonstrate similar binding profiles to that of the natural substrate, ACh. The affinities of VLB metabolites to dopaminergic and histaminic receptors, their absorption, distribution, metabolism, excretion, toxicity properties, and the superiority of VLB to ACh for binding to M5R, indicate their potential to trigger activation of nausea-associated receptors during chemotherapy with VLB. It has been shown that metabolite 20-hydroxy-VLB (metabolite 10) demonstrates a stronger binding affinity to the vinca site of tubulin than VLB; however, they have similar modes of action. VLB and metabolite 10 have similar gastric solubility (FaSSGF), intestinal solubility (FeSSIF), and log P values. Metabolite 10 has a more acceptable pharmacokinetic profile than VLB, a better gastric and intestinal solubility. Furthermore, metabolite 10 was found to be less bound to plasma proteins than VLB. These are desired and essential features for effective drug bioavailability. Metabolite 10 is not a substrate of CYP2D6 and thus is less likely to cause drug-drug interactions and ADRs compared to its parent drug. The hydroxyl group added upon metabolism of VLB suggests that it can also be a reasonable starting compound for designing the next generation of antimitotic drugs to overcome P-glycoprotein-mediated multidrug resistance, which is often observed with vinca alkaloids.

Dataset Information

Zerumbone, a cyclic sesquiterpene, exerts antimitotic activity in HeLa cells through tubulin binding and exhibits synergistic activity with vinblastine and paclitaxel.

Publications

Zerumbone, a cyclic sesquiterpene, exerts antimitotic activity in HeLa cells through tubulin binding and exhibits synergistic activity with vinblastine and paclitaxel.

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