Curcumin disrupts mitotic spindle structure and induces micronucleation in MCF-7 breast cancer cells.

摘要

The dietary phytochemical curcumin possesses anti-inflammatory, -oxidant, and cytostatic properties, and exhibits significant potential as a chemopreventative agent in humans. Although many cell types are arrested in the G2/M-phase of the cell cycle after curcumin treatment, the mechanisms by which this occurs are not well understood. The purpose of this study was to examine the effects of curcumin on the cell cycle of MCF-7 breast cancer cells to determine whether growth arrest is associated with structural changes in cellular organization during mitosis. For this purpose, MCF-7 breast cancer cells were treated with 10-20&mgr;M curcumin, and the effects on cell proliferation and mitosis studied. Structural changes were monitored by immunolabeling cells with antibodies to a number of cytoplasmic and nuclear proteins, including beta-tubulin, NuMA, lamins A/C and B1, lamin B receptor, and centromere antigens. At the concentrations used, a single dose of curcumin does not induce significant apoptosis, but is highly effective in inhibiting cell proliferation for over 6 days. During the first 24-48h of treatment, many cells are arrested in M-phase, and DNA synthesis is almost completely inhibited. Remarkably, arrested mitotic cells exhibit monopolar spindles, and chromosomes do not undergo normal anaphase movements. After 48h, most cells eventually leave M-phase, and many form multiple micronuclei instead of individual daughter nuclei. These observations indicate that the curcumin-induced G2/M arrest previously described for MCF-7 cells is due to the assembly of aberrant, monopolar mitotic spindles that are impaired in their ability to segregate chromosomes. The production of cells with extensive micronucleation after curcumin treatment suggests that at least some of the cytostatic effects of this phytochemical are due to its ability to disrupt normal mitosis, and raises the possibility that curcumin may promote genetic instability under some circumstances.