title: Induction of erythroid differentiation and increased globin mRNA production with furocoumarins and their photoproducts.
abstract: Differentiation-therapy is an important approach in the treatment of cancer, as in the case of erythroid induction in chronic myelogenous leukemia. Moreover, an important therapeutic strategy for treating beta-thalassemia and sickle-cell anemia could be the use of drugs able to induce erythroid differentiation and fetal hemoglobin (HbF) accumulation: in fact, the increased production of this type of hemoglobin can reduce the clinical symptoms and the frequency of transfusions. An important class of erythroid differentiating compounds and HbF inducers is composed by DNA-binding chemotherapeutics: however, they are not used in most instances considering their possible devastating side effects. In this contest, we approached the study of erythrodifferentiating properties of furocoumarins. In fact, upon UV-A irradiation, they are able to covalently bind DNA. Thus, the erythrodifferentiation activity of some linear and angular furocoumarins was evaluated in the experimental K562 cellular model system. Quantitative real-time reverse transcription polymerase-chain reaction assay was employed to evaluate the accumulation of different globin mRNAs. The results demonstrated that both linear and angular furocoumarins are strong inducers of erythroid differentiation of K562 cells. From a preliminary screening, we selected the most active compounds and investigated the role of DNA photodamage in their erythroid inducing activity and mechanism of action. Moreover, some cytofluorimetric experiments were carried out to better study cell cycle modifications and the mitochondrial involvement. A further development of the work was carried out studying the erythroid differentiation of photolysis products of these molecules. 5,5'-Dimethylpsoralen photoproducts induced an important increase in γ-globin gene transcription in K562 cells.
authors.affiliation: Department of Drug Sciences, University of Padova, Italy. alessia.salvador.1@unipd.it
authors.forename: Alessia
authors.initials: A
authors.lastname: Salvador
authors.forename: Eleonora
authors.initials: E
authors.lastname: Brognara
authors.forename: Daniela
authors.initials: D
authors.lastname: Vedaldi
authors.forename: Ignazio
authors.initials: I
authors.lastname: Castagliuolo
authors.forename: Paola
authors.initials: P
authors.lastname: Brun
authors.forename: Cristina
authors.initials: C
authors.lastname: Zuccato
authors.forename: Ilaria
authors.initials: I
authors.lastname: Lampronti
authors.forename: Roberto
authors.initials: R
authors.lastname: Gambari
mesh_terms: D002453:Cell Cycle; D002454:Cell Differentiation / Q000187:drug effects*; D002470:Cell Survival / Q000187:drug effects; D041905:Erythroid Cells / Q000166:cytology / Q000187:drug effects*; D011564:Furocoumarins / Q000737:chemistry / Q000494:pharmacology*; D005786:Gene Expression Regulation / Q000187:drug effects; D005914:Globins / Q000378:metabolism; D006801:Humans; D020014:K562 Cells; D008027:Light; D015394:Molecular Structure; D017319:Photosensitizing Agents / Q000737:chemistry / Q000494:pharmacology; D012333:RNA, Messenger / Q000378:metabolism*
chemical_list: D011564:Furocoumarins; D017319:Photosensitizing Agents; D012333:RNA, Messenger; D005914:Globins