title: Noncytotoxic differentiation treatment of renal cell cancer.
abstract: Current drug therapy for metastatic renal cell cancer (RCC) results in temporary disease control but not cure, necessitating continued investigation into alternative mechanistic approaches. Drugs that inhibit chromatin-modifying enzymes involved in transcription repression (chromatin-relaxing drugs) could have a role, by inducing apoptosis and/or through differentiation pathways. At low doses, the cytosine analogue decitabine (DAC) can be used to deplete DNA methyl-transferase 1 (DNMT1), modify chromatin, and alter differentiation without causing apoptosis (cytotoxicity). Noncytotoxic regimens of DAC were evaluated for in vitro and in vivo efficacy against RCC cell lines, including a p53-mutated RCC cell line developed from a patient with treatment-refractory metastatic RCC. The cell division-permissive mechanism of action-absence of early apoptosis or DNA damage, increase in expression of HNF4α (hepatocyte nuclear factor 4α), a key driver associated with the mesenchymal to epithelial transition, decrease in mesenchymal marker expression, increase in epithelial marker expression, and late increase in cyclin-dependent kinase inhibitor CDKN1B (p27) protein-was consistent with differentiation-mediated cell-cycle exit. In vivo blood counts and animal weights were consistent with minimal toxicity of therapy. The distinctive mechanism of action of a dose and schedule of DAC designed for noncytotoxic depletion of DNMT1 suggests a potential role in treating RCC.
authors.affiliation: Department of Translational Hematology and Oncology Research, Taussig Cancer Institute, Cleveland Clinic, Cleveland, Ohio, USA.
authors.forename: Soledad
authors.initials: S
authors.lastname: Negrotto
authors.forename: Zhenbo
authors.initials: Z
authors.lastname: Hu
authors.forename: Oscar
authors.initials: O
authors.lastname: Alcazar
authors.forename: Kwok Peng
authors.initials: KP
authors.lastname: Ng
authors.forename: Pierre
authors.initials: P
authors.lastname: Triozzi
authors.forename: Daniel
authors.initials: D
authors.lastname: Lindner
authors.forename: Brian
authors.initials: B
authors.lastname: Rini
authors.forename: Yogen
authors.initials: Y
authors.lastname: Saunthararajah
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D001374:Azacitidine / Q000031:analogs & derivatives / Q000494:pharmacology / Q000627:therapeutic use; D002292:Carcinoma, Renal Cell / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D002454:Cell Differentiation / Q000187:drug effects* / Q000235:genetics; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D016922:Cellular Senescence / Q000187:drug effects / Q000235:genetics; D003603:Cytotoxins / Q000494:pharmacology; D004249:DNA Damage / Q000187:drug effects; D000077209:Decitabine; D006801:Humans; D007680:Kidney Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D051379:Mice; D008819:Mice, Nude; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D003603:Cytotoxins; D000077209:Decitabine; D001374:Azacitidine