shogaol and pterostilbene

Breast cancer stem cells (BCSCs) constitute a small fraction of the primary tumor that can self-renew and become a drug-resistant cell population, thus limiting the treatment effects of chemotherapeutic drugs. The present study evaluated the cytotoxic effects of five phytochemicals including 6-gingerol (6-G), 6-shogaol (6-S), 5-hydroxy-3,6,7,8,3',4'-hexamethoxyflavone (5-HF), nobiletin (NOL), and pterostilbene (PTE) on MCF-7 breast cancer cells and BCSCs. The results showed that 6-G, 6-S, and PTE selectively killed BCSCs and had high sensitivity for BCSCs isolated from MCF-7 cells that expressed the surface antigen CD44(+)/CD24(-). 6-S and PTE induced cell necrosis phenomena such as membrane injury and bleb formation in BCSCs and inhibited mammosphere formation. In addition, 6-S and PTE increased the sensitivity of isolated BCSCs to chemotherapeutic drugs and significantly increased the anticancer activity of paclitaxel. Analysis of the underlying mechanism showed that 6-S and PTE decreased the expression of the surface antigen CD44 on BCSCs and promoted β-catenin phosphorylation through the inhibition of hedgehog/Akt/GSK3β signaling, thus decreasing the protein expression of downstream c-Myc and cyclin D1 and reducing BCSC stemness.

Topics: Antineoplastic Agents; Breast Neoplasms; Catechols; Cell Line, Tumor; Cell Proliferation; Cyclin D1; Female; Humans; Neoplastic Stem Cells; Oncogene Protein p55(v-myc); Signal Transduction; Stilbenes

Invadopodia are actin-rich membrane protrusions of tumor cells that are thought to initiate the local migration and invasion during cancer metastasis. The blockade of invadopodia-associated proteins has been reported as a promising approach for prevention of tumor metastasis. The aim of this study was to investigate the modulatory effects of 6-shogaol and pterostilbene on invadopodia in aggressive breast cancer cells.. By wound-healing, transwell, and gelatin zymography assays, we found that 6-shogaol and pterostilbene effectively attenuated the motility and invasion of MDA-MB-231 cells, and suppressed the activities of matrix metalloproteinase-2 (MMP-2) and matrix metalloproteinase-9 (MMP-9). Further investigation into the underlying molecular mechanisms revealed that the levels of key modulators of invadopodium maturation, including c-Src kinase, cortactin, and membrane type 1-matrix metalloproteinase (MT1-MMP) decreased when cells were treated with 6-shogaol or pterostilbene.. These data suggest that the repression of these factors might affect the maturation of invadopodia, inhibiting the metastasis of MDA-MB-231 cells. In conclusion, the present study demonstrates for the first time that 6-shogaol and pterostilbene can inhibit invadopodium formation and MMP activity in highly invasive breast cancer cells. We suggest that these compounds may be clinically useful in chemopreventive treatments for metastatic breast cancer.

Topics: Actins; Blotting, Western; Breast Neoplasms; Catechols; Cell Line, Tumor; Cell Movement; Cell Survival; Cortactin; CSK Tyrosine-Protein Kinase; Humans; Immunoprecipitation; Matrix Metalloproteinase 14; Matrix Metalloproteinase 2; Matrix Metalloproteinase 9; Nuclear Proteins; Receptor, Platelet-Derived Growth Factor alpha; RNA, Messenger; src-Family Kinases; Stilbenes; Twist-Related Protein 1