Inhibition of Cancer Stem-Like Phenotype by Curcumin and Deguelin in CAL-62 Anaplastic Thyroid Cancer Cells.

BACKGROUND: Anaplastic Thyroid Cancer (ATC) is one of the most lethal and aggressive human malignancies. Studies have shown that Cancer Stem-Cell (CSC) phenotype is mainly responsible for ATC aggressiveness. Cytostatic compounds are mostly ineffective because of multidrug resistance mechanisms driven by the CSC phenotype. Taxanes have limited efficacy. Recently, CSC inhibition using plant-derived, less toxic compounds, which have anti-cancer efficacy, has become a novel treatment modality. The aim of the study was to evaluate the anti-cancer activity of two natural compounds (curcumin and deguelin) on ATC cells and their CSC properties. In addition, the efficacies of these compounds were compared with that of docetaxel. METHODS: Besides control, five treatment groups were formed. ATC cells (CAL-62) were treated with curcumin, deguelin, docetaxel, and their combinations (curcumin+docetaxel, deguelin+docetaxel) at previously determined IC50 doses. Stemness was analyzed by quantitative estimation of sphere formation in matrigel, expression of several cell surface markers (CD133, CD90, Nanog, and OCT3/4) using flow cytometry, and quantification of the hypoxic status [Oxidative Stress Index (OSI) and Superoxide Dismutase (SOD) activity]. The anti-cancer efficacies of these compounds and their combinations were evaluated by determining the alterations in the cell cycle, apoptosis, and tumoral cell migration. RESULTS: Both the natural compounds (particularly curcumin) significantly suppressed the spheroid formation and cellular motility in matrigel as well as suppressed the accumulation of cells in the G0/1 phase, in which the maximum CSC activity is observed. The compounds did not suppress the expression of CSC markers, but twothirds of the cells expressed CD90. Deguelin was found to be particularly effective in inducing apoptosis similar to docetaxel at IC50 concentrations. Curcumin reduced the OSI and deguelin enhanced the SOD activity, even in docetaxel pre-treated cells. CONCLUSION: A large proportion of anaplastic tumors might consist of heterogeneous CSC population. Curcumin and deguelin have anti-cancer and several anti-stem cell activities against ATC cells. These natural compounds are capable of altering the aggressive behavior of ATC cells through the inhibition of the CSC phenotype. As a novel therapeutic target, CD90 should be investigated in other ATC cell lines and in vivo models.

Human chorionic gonadotropin (hCG) prevents the transformed phenotypes induced by 17 beta-estradiol in human breast epithelial cells.

Human chorionic gonadotropin (hCG), a hormone produced during pregnancy, can elicit life-long refractoriness to carcinogenesis by differentiation of the breast epithelium. Human breast epithelial cells MCF-10F form tubules in collagen, mimicking the normal ductules. We have shown that 17 beta-estradiol (E2) alter the ductulogenic pattern of these cells. The effect of the recombinant hCG (rhCG) in vitro was evaluated on the transformation of MCF-10F induced by E2. MCF-10F cells were treated with 70 nM E2 alone or in combination with 50 IU/ml rhCG during 2 weeks, while the controls were treated with DMSO (the solvent in which E2 was dissolved) or rhCG alone. At the end of treatment, the cells were plated in type I collagen matrix (3D-cultures) for detecting 2 main phenotypes of cell transformation, namely the loss of ductulogenic capacity and the formation of solid masses. Although E2 significantly increased solid mass formation, this effect was prevented when MCF-10F cells were treated with E2 in combination with rhCG. Furthermore, E2 increased the main duct width (p < 0.001), and caused a disruption of the luminal architecture, whereas rhCG increased the length of the tubules (p < 0.001) and produced tertiary branching. In conclusion, rhCG was able to abrogate the transforming abilities of estradiol, and had the differentiating property by increasing the branching of the tubules formed by breast epithelial cells in collagen. These results further support our hypothesis, known as the terminal differentiation hypothesis of breast cancer prevention, that predicts that hCG treatment results in protection from tumorigenic changes by the loss of susceptible stem cells 1 through a differentiation to refractory stem cells 2 and increase differentiation of the mammary gland.

Primary non-hodgkin lymphoma of breast in a patient with rectal carcinoma and magnetic resonance spectroscopic examination.

A 62-year-old woman being treated for stage IIIC rectal adenocarcinoma was diagnosed with primary non-Hodgkin lymphoma of the breast after a 4-year follow-up. This case illustrates the importance of close and long-term follow-up as well as of differential diagnostic procedures for second primary malignancies after the initial diagnosis and treatment of a solid tumor.