RESUMO
We have previously reported that high aldehyde dehydrogenase (ALDH) enzyme activity in breast cancer cells results in breast cancer stem cell (BCSC) properties by upregualting Notch-1 and epithelial mesenchymal markers. This results in chemoresistance in breast cancer. Here, we examined the functional and clinical significance of ALDH expression by measuring the ALDH levels in breast cancer tissues by immunohistochemistry. There was a significantly higher ALDH expression in higher grade breast cancer tumor tissues (Grade- II and III) versus normal breast tissues. Injection of BCSC (ALDH+ and CD44+ /CD22- ) cells resulted in aggressive tumor growth in athymic mice versus ALDH- cells. The ALDH+ and CD44+ /CD22- tumors grow rapidly and are larger than ALDH- tumors which were slow growing and smaller. Molecularly, ALDH+ tumors expressed higher expression of Notch-1 and EMT markers than ALDH- tumors. Oral administration of the naturally occurring Psoralidin (Pso, 25 mg/kg of body weight) significantly inhibited the growth in ALDH+ and ALDH- tumors as well. Psoralidin inhibited Notch-1 mediated EMT activation in ALDH+ and ALDH- tumors-this confirms our in vitro findings. Our results suggest that Notch-1 could be an attractive target and inhibition of Notch-1 by Psoralidin may prevent pathogenesis of breast cancer as well as metastasis. © 2016 Wiley Periodicals, Inc.
Assuntos
Aldeído Desidrogenase/metabolismo , Benzofuranos/administração & dosagem , Neoplasias da Mama/tratamento farmacológico , Cumarínicos/administração & dosagem , Células-Tronco Neoplásicas/efeitos dos fármacos , Receptor Notch1/metabolismo , Animais , Benzofuranos/farmacologia , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Linhagem Celular Tumoral , Cumarínicos/farmacologia , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Feminino , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Camundongos , Gradação de Tumores , Células-Tronco Neoplásicas/metabolismo , Células-Tronco Neoplásicas/patologia , Transdução de Sinais/efeitos dos fármacos , Regulação para Cima/efeitos dos fármacos , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Conjugated linoleic acid (cLA) is a commercially available weight-loss supplement that is not currently regulated by the U.S. FDA. Numerous studies suggest that cLA mediates protection against diseases including cancer, diabetes, atherosclerosis, immune function, and obesity. Based upon these reports, it was hypothesized that supplementation with cLA would improve heart function in aged wild-type (WT) mice. At 10 months of age, mice were treated with cLA, nitrite, or the combination of the two. Echocardiograms revealed that cardiac function was decreased in aged compared to young WT mice, as determined by percentage of fractional shortening. Also, contrary to the hypothesis, mice that received cLA (6-week treatment) had significantly worse cardiac function compared to controls. This effect was attenuated when mice were cotreated with cLA and nitrite. Taken together, these results suggest that cLA-mediated cardiac injury can be circumvented by nitrite supplementation in a murine model of aging.