nutlin-3a and Adenocarcinoma

Topics: Adenocarcinoma; Apoptosis; Aurora Kinase B; CDC2 Protein Kinase; Cell Cycle Checkpoints; Cell Line, Tumor; Cyclin-Dependent Kinase Inhibitor p21; Humans; Imidazoles; Male; Piperazines; Prostatic Neoplasms; Proto-Oncogene Proteins c-mdm2

Lung adenocarcinoma accounts for ∼40% of lung cancers, the leading cause of cancer-related death worldwide, and current therapies provide only limited survival benefit. Approximately half of lung adenocarcinomas harbor mutations in

Topics: Adenocarcinoma; Adenocarcinoma of Lung; Animals; Antineoplastic Agents; Cell Cycle Checkpoints; Cell Death; Cell Line, Tumor; Disease Models, Animal; Drug Resistance, Neoplasm; Gene Expression Regulation, Neoplastic; Genotype; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Imidazoles; Lung Neoplasms; Mice; Molecular Targeted Therapy; Mutation; Piperazines; Simvastatin; Tumor Suppressor Protein p53

Heat-shock protein 90 (Hsp90) is highly expressed in many tumor cells and is associated with the maintenance of malignant phenotypes. Targeting Hsp90 has had therapeutic success in both solid and hematological malignancies, which has inspired more studies to identify new Hsp90 inhibitors with improved clinical efficacy. Using a fragment-based approach and subsequent structural optimization guided by medicinal chemistry principles, we identified the novel compound CPUY201112 as a potent Hsp90 inhibitor. It binds to the ATP-binding pocket of Hsp90 with a kinetic dissociation (Kd) constant of 27 ± 2.3 nM. It also exhibits potent in vitro antiproliferative effects in a range of solid tumor cells. In MCF-7 cells with high Hsp90 expression, CPUY201112 induces the degradation of Hsp90 client proteins including HER-2, Akt, and c-RAF. We prove that treating MCF-7 cells with CPUY201112 results in cell cycle arrest and apoptosis through the wild-type (wt) p53 pathway. CPUY201112 also synergizes with Nutlin-3a to induce cancer cell apoptosis. CPUY201112 significantly inhibited the growth of MCF-7 xenografts in nude mice without apparent body weight loss. These results demonstrate that CPUY201112 is a novel Hsp90 inhibitor with potential use in treating wild-type p53 related cancers.

Topics: Adenocarcinoma; Animals; Antineoplastic Agents; Breast Neoplasms; Drug Synergism; Female; Gene Expression Regulation, Neoplastic; HSP90 Heat-Shock Proteins; Humans; Imidazoles; MCF-7 Cells; Mice; Mice, Nude; Piperazines; Proteolysis; Proto-Oncogene Proteins c-akt; Proto-Oncogene Proteins c-raf; Pyrimidines; Receptor, ErbB-2; Resorcinols; Signal Transduction; Tumor Burden; Tumor Suppressor Protein p53; Xenograft Model Antitumor Assays

Loss of Pten in the Kras(G12D);Amhr2-Cre mutant mice leads to the transformation of ovarian surface epithelial (OSE) cells and rapid development of low-grade, invasive serous adenocarcinomas. Tumors occur with 100% penetrance and express elevated levels of wild-type tumor repressor protein 53 (TRP53). To test the functions of TRP53 in the Pten;Kras (Trp53+) mice, we disrupted the Trp53 gene yielding Pten;Kras(Trp53-) mice. By comparing morphology and gene expression profiles in the Trp53+ and Trp53- OSE cells from these mice, we document that wild-type TRP53 acts as a major promoter of OSE cell survival and differentiation: cells lacking Trp53 are transformed yet are less adherent, migratory, and invasive and exhibit a gene expression profile more like normal OSE cells. These results provide a new paradigm: wild-type TRP53 does not preferentially induce apoptotic or senescent related genes in the Pten;Kras(Trp53+) cancer cells but rather increases genes regulating DNA repair, cell cycle progression, and proliferation and decreases putative tumor suppressor genes. However, if TRP53 activity is forced higher by exposure to nutlin-3a (a mouse double minute-2 antagonist), TRP53 suppresses DNA repair genes and induces the expression of genes that control cell cycle arrest and apoptosis. Thus, in the Pten;Kras(Trp53+) mutant mouse OSE cells and likely in human TP53+ low-grade ovarian cancer cells, wild-type TRP53 controls global molecular changes that are dependent on its activation status. These results suggest that activation of TP53 may provide a promising new therapy for managing low-grade ovarian cancer and other cancers in humans in which wild-type TP53 is expressed.

Topics: Adenocarcinoma; Animals; Apoptosis; Cell Cycle; Cell Differentiation; Cell Line, Tumor; Cell Proliferation; Cell Survival; Cells, Cultured; Disease Models, Animal; Female; Gene Expression Regulation, Neoplastic; Humans; Imidazoles; Mice; Mice, Knockout; Ovarian Neoplasms; Piperazines; Tumor Suppressor Protein p53