Inhibition of bromodomain and extraterminal domain reduces growth and invasive characteristics of chemoresistant ovarian carcinoma cells.

Epithelial ovarian cancer (EOC) is the most lethal gynecological malignancy worldwide. Development of chemoresistance and peritoneal dissemination are the major reasons for low survival rate in the patients. The bromodomain and extraterminal domain (BET) proteins are known as epigenetic 'readers,' and their inhibitors are novel epigenetic strategies for cancer treatment. Accumulating body of evidence indicates that epigenetic modifications have critical roles in development of EOC, and overexpression of the BET family is a key step in the induction of important oncogenes. Here, we examined the mechanistic activity of I-BET151, a pan-inhibitor of the BET family, in therapy-resistant EOC cells. Our findings showed that I-BET151 diminished cell growth, clonogenic potential, and induced apoptosis. I-BET151 inhibited cell proliferation through down-modulation of FOXM1 and its targets aurora kinase B and cyclin B1. I-BET151 attenuated migration and invasion of the EOC cells by down-regulation of epithelial-mesenchymal transition markers fibronectin, ZEB2, and N-cadherin. I-BET151 synergistically enhanced cisplatin chemosensitivity by down-regulation of survivin and Bcl-2. Our data provide insights into the mechanistic activity of I-BET151 and suggest that BET inhibition has potential as a therapeutic strategy in therapy-resistant EOC. Further in vivo investigations on the therapeutic potential of I-BET151 in EOC are warranted.

Silibinin affects tumor cell growth because of reduction of stemness properties and induction of apoptosis in 2D and 3D models of MDA-MB-468.

Silibinin, with a strong antioxidant activity and a weak cytotoxic property, is considered a candidate for cancer prevention. As there is no information on its effect on breast cancer tumor-initiating cells [cancer stem cells (CSCs)] in a 3D culture model, which more closely mimic natural tissues, we carried out this study to determine whether silibinin can target breast CSCs in MDA-MB-468 cells cultured under 3D and 2D conditions. Silibinin was added to culture medium of MDA-MB-468 at a half maximal inhibitory concentration (IC50) dose in 2D and 3D models. Then, stemness properties were assessed using colony and sphere-formation tests. Flow cytometry and real-time PCR were used to determine the different expression levels of stem cell-related marker at protein and mRNA levels under both culture conditions. Our results showed that silibinin inhibits cell growth in a dose-dependent manner by induction of apoptosis, alteration of the cell cycle, reduction of stemness properties and function, and induction of tumoral differentiation. The mechanism of silibinin action and also the response of tumor cells differed when cells were cultured in a 3D model compared with a 2D model. Silibinin may potentially target breast CSCs. Moreover, tumor-initiating cells are more sensitive to silibinin in a 3D culture than in a 2D culture.