title: Actual targets in cytodifferentiation cancer therapy.
abstract: Transformation of a normal cell into a tumor cell results from six essential alterations in cell physiology. There is a complex relationship that exists between growth, differentiation, neoplastic transformation, and the expression of genes and tumor suppressor genes. The knowledge of these mechanisms demonstrates that it is possible to pharmacologically modulate the growth and differentiation of tumor cells. The differentiation therapy focuses on demonstrating that cancer is a reversible state with altered maturation in which the transformed phenotype may be suppressed by cytostatic agents and by the pharmacological differentiation towards benign forms with no proliferative potential. One of the mechanisms determining the activity of target genes is the post-translational modification of the N-terminal tails of core histones. Inappropriate repression of genes required for cell differentiation has been linked to several forms of cancer. Histone deacetylase inhibitors modulate transcription, and are endowed with cytodifferentiating, antiproliferative and apoptogenic properties. Retinoids modulate cell differentiation, proliferation, apoptosis and morphogenesis in vertebrates, and have proved to be clinically useful. Their biological effects are mediated by the activation of retinoic acid receptors, which are ligand-dependent gene transcription factors. Checkpoints during cell cycle allow the cell to respond to proliferation signals or decide between the alternate pathways leading to cytokinesis, differentiation, quiescence, and cell death. Abrogation of normal cell cycle controls in tumor cells contributes to their inability to differentiate and the restoration of such controls in G1 can lead to the resumption of differentiation and terminal cell division. Chemical inhibitors of cyclin-dependent kinases have been reported to stimulate differentiation of tumor-cell lines.
authors.affiliation: Departamento de Química Farmacéutica y Orgánica, Universidad de Granada, 18071 Granada, Spain.
authors.forename: José A
authors.initials: JA
authors.lastname: Gómez-Vidal
authors.forename: Joaquín
authors.initials: J
authors.lastname: Campos
authors.forename: Juan A
authors.initials: JA
authors.lastname: Marchal
authors.forename: Houria
authors.initials: H
authors.lastname: Boulaiz
authors.forename: Miguel A
authors.initials: MA
authors.lastname: Gallo
authors.forename: Esmeralda
authors.initials: E
authors.lastname: Carrillo
authors.forename: Antonio
authors.initials: A
authors.lastname: Espinosa
authors.forename: Antonia
authors.initials: A
authors.lastname: Aránega
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use* / Q000633:toxicity; D002454:Cell Differentiation; D018844:Cyclin-Dependent Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D056572:Histone Deacetylase Inhibitors; D006655:Histone Deacetylases / Q000378:metabolism; D006801:Humans; D009369:Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology*; D018160:Receptors, Cytoplasmic and Nuclear / Q000037:antagonists & inhibitors / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D056572:Histone Deacetylase Inhibitors; D018160:Receptors, Cytoplasmic and Nuclear; D018844:Cyclin-Dependent Kinases; D006655:Histone Deacetylases