Abstract
ObjectivesThe 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 methodsHeLa 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.ResultsZerumbone selectively inhibited the proliferation of HeLa cells with an IC50 of 14.2 ± 0.5 μmol/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 μmol/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 μmol/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.ConclusionOur 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.
Highlights
Cancer is one of the leading causes of death all over the world, and cancer treatment remains one of the greatest challenges in front of the healthcare professionals.[1,2] Most of the anti‐cancer agents cur‐ rently available in the market are non‐selective and could destroy the normal healthy cells
We found that the uptake of fluorozerumbone by Human cervical cancer cell line (HeLa) cells was 26 nmol/cell and that by L929 cells was 14.8 nmol/cell
Results from liquid chromatography‐mass spectrometry (LC‐MS) and Nuclear Magnetic Resonance spectroscopy (NMR) were in conformity with the mo‐ lecular weight (218.34) and the structure of the compound
Summary
Cancer is one of the leading causes of death all over the world, and cancer treatment remains one of the greatest challenges in front of the healthcare professionals.[1,2] Most of the anti‐cancer agents cur‐ rently available in the market are non‐selective and could destroy the normal healthy cells. Mammalian cell division requires the coordinated actions of the cytoskeleton, the membrane proteins, the motor proteins and the cell cycle regulatory proteins which are precisely controlled in space and time.[4,5] Among the various players in cell division, tubulin is indispensable for mito‐ sis and chromosome segregation, and antimitotic agents targeting tubulin are the most successful in the treatment of various types of tumours.[5,6] The other essential antimitotic targets include the mi‐ totic kinesins such as Eg5, CENP‐E, MCAK, and MKLP1; the mitotic
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