n-(n-(3-5-difluorophenacetyl)alanyl)phenylglycine-tert-butyl-ester and Carcinogenesis

Notch is a key player in various developmental processes during the embryonic stage as well as in regulating tissue homeostasis, cell differentiation, and stem cell maintenance in adult life. Activation of Notch signaling occurs following Notch receptor-ligand interaction and subsequent enzymatic proteolysis by the gamma-secretase complex, resulting in the cytoplasmic release of a Notch intracellular domain, which translocates to the nucleus to initiate the downstream transcriptional machinery. Notch activation and its aberrant signaling have been broadly linked to the pathogenesis of cancer and some chronic inflammatory diseases resulting in pathologic fibrotic processes. This review focuses on the molecular basis of Notch-induced signaling and its interaction with other pathways to identify therapeutic targets. We also highlight current efforts to pharmacologically intervene in Notch signaling and discuss promising ongoing experimental and clinical studies.

Topics: Amyloid Precursor Protein Secretases; Animals; Anti-Inflammatory Agents; Antineoplastic Agents; Carcinogenesis; Clinical Trials as Topic; Fibrosis; Genes, Tumor Suppressor; Humans; Inflammation; Ligands; Neoplasms; Receptors, Notch; Signal Transduction

Notch signaling is implicated in ovarian cancer tumorigenesis and inhibition of Notch signaling with γ-secretase inhibitor DAPT resulted in reduction of tumor cell viability and induction of apoptosis in ovarian cancer cells. This study investigated whether DAPT has the same effect on ovarian cancer cells that are resistant to cisplatin and the underlying molecular events. Ovarian cancer cell lines resistant to cisplatin were treated with DAPT, cisplatin or combination for cell viability MTT, flow cytometric cell cycle, ELISA apoptosis and colony formation assays. qRT-PCR and western blotting were used to detect gene expressions. We found that pretreatment of ovarian cancer cisplatin-resistant cell lines with DAPT for 24 h and then with cisplatin for 72 h showed a synergistic antitumor activity in these cell lines, while cisplatin treatment and then addition of DAPT just showed an additive or antagonistic effects on these cisplatin-resistant ovarian cancer cells. Moreover, pretreatment of ovarian cancer cell lines with DAPT and then with cisplatin also inhibited tumor cell colony formation capacity, arrested tumor cells at G2 phase of the cell cycle and induced apoptosis. The cell cycle and apoptosis-related genes, such as cyclin B1, Bcl-2 and caspase-3, were also modulated by the treatment. Pretreatment of ovarian cancer cell lines with DAPT and then with cisplatin downregulated Notch1 and Hes1 expression dose- and time-dependently. The current data demonstrate that DAPT pretreatment was able to sensitize cisplatin-resistant human ovarian cancer cells to cisplatin by downregulation of Notch signaling.

Topics: Amyloid Precursor Protein Secretases; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Apoptosis; Basic Helix-Loop-Helix Transcription Factors; Carcinogenesis; Caspase 3; Cell Line, Tumor; Cell Survival; Cisplatin; Cyclin B1; Dipeptides; Down-Regulation; Drug Resistance, Neoplasm; Drug Synergism; Female; G2 Phase Cell Cycle Checkpoints; Homeodomain Proteins; Humans; Ovarian Neoplasms; Proto-Oncogene Proteins c-bcl-2; Receptor, Notch1; Signal Transduction; Transcription Factor HES-1