RESUMEN
Triple-negative breast cancer (TNBC) is a breast cancer subtype that has an aggressive phenotype, is highly metastatic, has limited treatment options and is associated with a poor prognosis. In addition, metastatic TNBC has no preferred standard chemotherapy due to resistance to anthracyclines and taxanes. The present study demonstrated that a herbal extract, SH003, reduced cell viability and induced apoptosis in TNBC without cell cytotoxicity. Cell viability was examined using trypan blue exclusion and colony formation assays, which revealed a decrease in the cell viability. Additionally, apoptosis was determined using flow cytometry and a subG1 assay, which revealed an increase in the proportion of cells in the subG1 phase. The present study investigated the anticancer effect of SH003 in the Hs578T, MDAMB231 and ZR751 TNBC cell lines, and in the MCF7 and T47D nonTNBC cell lines. Western blot analysis revealed that the expression levels of polyADPribose polymerase (PARP) cleavage protein in cells treated with SH003 were increased dosedependent manner, indicating that SH003 induced apoptosis via a caspasedependent pathway. Pretreatment with the caspase inhibitor ZVAD reduced SH003induced apoptosis was examined using trypan blue exclusion. Moreover, SH003 treatment enhanced the p73 levels in MDAMB231 cells but not in MCF7 cells. Transfection of p73 small interfering RNA (siRNA) in MDAMB0231 cells revealed that the apoptotic cell death induced by SH003 was significantly impaired in comparison with scramble siRNA transfected MDAMB231 cells. This was examined using trypan blue exclusion and flow cytometry analysis (subG1). In addition, SH003 and paclitaxel exhibited synergistic anticancer effects on TNBC cells. The results indicate that SH003 exerts its anticancer effect via p73 protein induction and exhibits synergistic anticancer effects when combined with paclitaxel.
Asunto(s)
Antineoplásicos Fitogénicos/farmacología , Apoptosis/efectos de los fármacos , Extractos Vegetales/farmacología , Neoplasias de la Mama Triple Negativas/tratamiento farmacológico , Proteína Tumoral p73/metabolismo , Angelica , Planta del Astrágalo , Mama/efectos de los fármacos , Mama/metabolismo , Mama/patología , Caspasas/metabolismo , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Resistencia a Antineoplásicos/efectos de los fármacos , Femenino , Humanos , Paclitaxel/farmacología , Trichosanthes , Neoplasias de la Mama Triple Negativas/metabolismo , Neoplasias de la Mama Triple Negativas/patologíaRESUMEN
PKCη is involved in proliferation, differentiation, and drug resistance. However, PKCη function in EBV(+) B lymphoma remains poorly understood. Gene silencing of PKCη through siRNA knockdown inhibited cellular proliferation, induced cell cycle arrest in G0/G1 and G2/M phases, and sensitized cells to chemotherapeutic drugs. Upon PKCη knockdown, expression levels of p21, GADD45α, and TAp73 were all increased, whereas expression levels of CDK2, CDK4, CDK6, cyclin E, cyclin B1, and cdc2 were all downregulated. PKCη silencing also activated p38-MAPK, which in turn contributed to the expression of cell cycle arrest-related molecules. These results suggest that siRNA-mediated silencing of PKCη can be a potent tool to complement existing chemotherapy regimens for treating EBV(+) B lymphoma.
Asunto(s)
Antineoplásicos/uso terapéutico , Linfoma de Burkitt/tratamiento farmacológico , Resistencia a Antineoplásicos/genética , Herpesvirus Humano 4 , Proteína Quinasa C/genética , Apoptosis/efectos de los fármacos , Apoptosis/genética , Ácidos Borónicos/uso terapéutico , Bortezomib , Linfoma de Burkitt/genética , Puntos de Control del Ciclo Celular/genética , Proteínas de Ciclo Celular/biosíntesis , División Celular/genética , Línea Celular Tumoral , Proliferación Celular , Inhibidor p21 de las Quinasas Dependientes de la Ciclina/biosíntesis , Inhibidor p21 de las Quinasas Dependientes de la Ciclina/genética , Proteínas de Unión al ADN/biosíntesis , Humanos , Potencial de la Membrana Mitocondrial , FN-kappa B/genética , Niacinamida/análogos & derivados , Niacinamida/uso terapéutico , Proteínas Nucleares/biosíntesis , Compuestos de Fenilurea/uso terapéutico , Fosfatidilinositol 3-Quinasas/genética , Proteína Quinasa C/metabolismo , Pirazinas/uso terapéutico , Interferencia de ARN , ARN Interferente Pequeño/genética , Sorafenib , Proteína Tumoral p73 , Proteínas Supresoras de Tumor/biosíntesis , Regulación hacia Arriba , Proteínas Quinasas p38 Activadas por Mitógenos/biosíntesisRESUMEN
Melanoma is an aggressive form of skin cancer due to its rapid metastasis. Recently, several studies have reported that selenium can prevent metastasis of melanoma cells, but the mechanism of this anti-metastatic ability is not fully understood. In this study, we investigated the effect of selenium on cell migration in melanoma and on tumor metastasis in mice. Interestingly, tumor metastasis was suppressed by selenium in a mouse model. Cell migration was measured by a wound-healing assay using selenium-treated melanoma cells. Treatment with a non-cytotoxic concentration of selenium suppressed migration of melanoma cells in a dose-dependent manner. In addition, we found decreased HIF-1α and VEGF expression in selenium-treated melanoma cells as compared to non-treated control cells. Mechanistically, our studies show that selenium inhibits IL-18 gene expression in a dose-dependent manner. IL-18 protein level was suppressed by treatment with selenium. The wound-healing assay revealed that the anti-metastatic effect of selenium was abrogated by treatment with exogenous IL-18. These results suggest that selenium might be a potent inhibitor of the metastatic capacity of melanoma cells, via down-modulation of IL-18 expression.