gsk1210151a and Ovarian-Neoplasms

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.

Topics: Antineoplastic Combined Chemotherapy Protocols; Apoptosis; Carcinoma, Ovarian Epithelial; Cell Line, Tumor; Cell Movement; Cell Proliferation; Cisplatin; Down-Regulation; Drug Resistance, Neoplasm; Drug Synergism; Epigenesis, Genetic; Epithelial-Mesenchymal Transition; Female; Heterocyclic Compounds, 4 or More Rings; Humans; Ovarian Neoplasms; Proteins

Ovarian cancer (OC) is a common malignant tumor with a high probability of metastasis. Thus, it is urgently necessary to develop new drugs that inhibit tumor metastasis. Bromodomain and extraterminal (BET) inhibitors targeting bromodomain-containing proteins are currently recognized as novel anticancer agents. Herein, we explored the effects of i-BET151, a BET bromodomain inhibitor, on OC metastasis and on antitumor immunity. Our experiments showed that i-BET151 decreased the viability and induced apoptosis, senescence, and cell cycle arrest of cancer cells. In addition, phosphorylated-Stat3 (Tyr705) amounts OC cell invasion and migration, and expression of matrix metalloproteinases (MMP-9 and MMP-2) decreased. Moreover, tumor metastasis in the abdomen of the OC model was inhibited by i-BET151. Notably, i-BET151-promoted immunogenic cell death (ICD) was confirmed in vivo; it was demonstrated with ICD markers. Furthermore, treatment with i-BET151 promoted infiltration by CD8

Topics: Animals; Apoptosis; Bcl-2-Like Protein 11; Cell Line, Tumor; Cell Movement; Cell Proliferation; Female; Heterocyclic Compounds, 4 or More Rings; Humans; Immunity; Mice, Inbred BALB C; Neoplasm Invasiveness; Neoplasm Metastasis; Ovarian Neoplasms; Up-Regulation

Ovarian cancer is responsible for the highest mortality among all gynecologic malignancies, and novel therapies are urgently needed to improve patient outcome. Here we performed an integrative genomic analysis and identified the bromodomain and extraterminal domain (BET) protein BRD4 as a potential therapeutic target in ovarian cancer. Suppression of BRD4 using small-molecule BET inhibitors JQ1 and I-BET151, or dual kinase-bromodomain inhibitor volasertib, led to robust and broad antitumor effects across all subclasses of ovarian cancer. In contrast to many other cancers which are susceptible to BET inhibition due to downregulation of super-enhancer-dependent MYC transcript, we discovered that JQ1-sensitive ovarian cancer cells exhibited marked disruption of Forkhead box protein M1 (FoxM1) pathway, a key driver of ovarian carcinoma. These in vitro findings were further supported by in vivo efficacies of JQ1 targeting both cell line-based and patient-derived xenograft models. Our data establish a new treatment strategy against ovarian cancer by employing epigenetic vulnerabilities, and provide a mechanistic rationale for the clinical investigation of BET bromodomain inhibitors in this deadly disease.

Topics: Animals; Antineoplastic Agents; Azepines; Carcinoma; Cell Line, Tumor; Down-Regulation; Female; Forkhead Box Protein M1; Heterocyclic Compounds, 4 or More Rings; Humans; Mice; Mice, Inbred BALB C; Mice, Nude; Nuclear Proteins; Ovarian Neoplasms; Pteridines; Transcription Factors; Triazoles