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Curcumolhas been reported to possess antitumor activity. However, its effect and mechanisms against tumor metastasis are still unclear. This study is to investigate the inhibitory effect of curcumol on breast cancer cell metastasis and elucidate the underlying molecular mechanisms. Our results showed that noncytotoxicity was caused by curcumol within 10 to 40 µg/mL in MDA-MB-231 and 4T1 cells for 24 hours, whereas sustained treatment with curcumol for 14 days significantly suppressed the clonogenic activity of cells. Importantly, curcumol at noncytotoxic concentrations suppressed the migration ability of both MDA-MB-231 and 4T1 cells. Moreover, curcumol suppressed the migration and invasion of MDA-MB-231 cells in the Boyden chamber migration and invasion assay and inhibited the adhesion of MDA-MB-231 cells onto the matrigel. Further investigations revealed that curcumol decreased the enzyme activity and protein expression of matrix metalloproteinase (MMP-9) in MDA-MB-231 cells. Moreover, curcumol inhibited the activation of c-Jun N-terminal kinase (JNK) 1/2 and Akt (Ser473). Meanwhile, it also inhibited the nuclear translocation and transcriptional activity of nuclear factor κB (NF-κB). Furthermore, JNK inhibitor SP600125 and Akt (Ser473) inhibitor LY294002 enhanced the inhibition of curcumol on NF-κB p65 nuclear translocation. Finally, supplementation with SP600125, LY294002, or NF-κB inhibitor Ammonium pyrrolidinedithiocarbamate (PDTC) significantly enhanced the inhibitory effect of curcumol on MMP-9 expression and cell migration, invasion, and adhesion in MDA-MB-231 cells. Our findings provide evidence for the suppression of breast cancer cell metastasis by curcumol and suggest that the inhibition of MMP-9 via JNK1/2 and Akt (Ser473)-dependent NF-κB signaling pathways may be the underlying mechanisms.

Key words Z-ligustilide; heat-shock protein 70; mitogen-activated protein kinase; oxygen-glucose deprivation-reoxygenation; heat-shock factor 1The World Health Organization (WHO) Global Infobase reports that stroke has become the second leading cause of mortality in the world, causing around 6000000 deaths annually. 1)However, there are currently relatively few treatment options available to minimize damage or death following a stroke. Protein aggregates containing ubiquitinated proteins are commonly present in neurodegenerative disorders and have been considered to cause neuronal degeneration. The previous study also showed that transient cerebral ischemia caused severe protein aggregation in hippocampal CA1 neurons which appeared at 4 h and progressively accumulated at 24 and 48 h. 2)Therefore, control of protein aggregation may represent an alternative treatment to neurological damage caused by ischemic stroke.Heat shock proteins (HSPs) are a group of phylogenetically and ubiquitous cytoprotective proteins found in all prokaryotic and eukaryotic cells, many of which are chaperone molecules that facilitate protein folding, trafficking and also prevent their aggregation and degradation.3) Heat shock protein 70 (HSP70) is a major inducible heat shock protein that basically functions as a molecular chaperone and plays an important role in preventing protein aggregation, degrading unstable and misfolded proteins and transporting proteins between cellular compartments.4) It's reported that over-expression of HSP70 via transgenes and viruses or systemic administration of HSP70 fusion proteins that allow it to cross the blood brain barrier protects the brain against ischemia, 5,6) suggesting that increasing HSP70 level or activity may be a potential therapeutic target for pharmacological intervention of ischemic diseases.Ligusticum chuanxiong is a commonly used Chinese herbal medicine with its empiric treatment of cardiovascular and cerebrovascular diseases.7) Z-Ligustilide as the major bioactive phthalide compound of Rhizoma chuanxiong was previously suggested for the prevention and treatment of ischemic stroke. 8,9) Our and others' studies showed that Z-ligustilide could protect ischemic injury both in vitro and in vivo via the induction of direct and indirect antioxidant response. 8,10,11) However, its effect on the heat shock response, a highly conserved and fundamental cytoprotective mechanism, under ischemic stress remains unexplored. Along this line, we characterized the effect of Z-ligustilide on HSP70 and explored the potential role of HSP70 in the protection of Z-ligustilide against oxygen-glucose deprivation and reoxygenation (OGDReoxy) induced injury in this study.

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Acori Graminei Rhizoma is well known for the beneficial effects on CNS disorders in traditional medicine. Though it is frequently prescribed in formulations for brain tumors, the anti-glioma effect has not been examined. We used volatile oil of Acori Graminei Rhizoma (VOA) and human glioblastoma multiforme (GBM) cells in this study. We found that VOA exhibited greater growth suppression in p53 wild-type cells than p53 mutant cells and very low effect on fibroblasts and human glial HEB cells. Apoptosis was triggered by VOA with a caspase-dependent way in p53 wild-type A172 cells, while a caspase-independent way in p53 mutant U251 cells. Meanwhile, both A172 and U251 cells treated by VOA displayed autophagic features. Furthermore, p53 decrease was observed along with VOA-induced apoptosis and autophagy in A172 cells. VOA-induced autophagy was mediated through a p53/AMPK/mTOR signaling pathway in A172 cells, while an mTOR-independent signaling pathway in U251 cells. Finally, blockage of autophagy potentiated the proapoptotic effect in both A172 and U251 cells, indicating a protective role of autophagy in VOA-induced cell death. Together, VOA exhibited anti-tumor activity in human GBM cells and induced apoptotic cell death and protective autophagy, which is cell type specific and dependent on p53 status.