Effects on erythroid differentiation of platinum(II) complexes of synthetic bile acid derivatives

• Published in: Bioorganic & medicinal chemistry Vol. 14; no. 15; pp. 5204 - 5210
• Main Authors: Lampronti, Ilaria, Bianchi, Nicoletta, Zuccato, Cristina, Medici, Alessandro, Bergamini, Paola, Gambari, Roberto
• Format: Journal Article
• Language: English
• Published: Oxford Elsevier Ltd 01.08.2006; Elsevier Science
• Subjects: Bile acid derivatives; Bile Acids and Salts - chemical synthesis; Bile Acids and Salts - chemistry; Bile Acids and Salts - pharmacology; Biological and medical sciences; Cell Differentiation - drug effects; Cell Proliferation - drug effects; Erythroid differentiation; Erythroid Precursor Cells - cytology; Erythroid Precursor Cells - drug effects; Fetal hemoglobin; Globins - chemistry; Globins - drug effects; Humans; K562 Cells; Medical sciences; Miscellaneous; Organoplatinum Compounds - chemical synthesis; Organoplatinum Compounds - chemistry; Organoplatinum Compounds - pharmacology; Pharmacology. Drug treatments; Platinum complexes; RNA, Messenger - biosynthesis; RNA, Messenger - drug effects; Structure-Activity Relationship; β-Thalassemia; γ-Globin; RT; EPO; γ-Globin; HbF; HU; Ara-C; Fetal hemoglobin; BSA; β-Thalassemia; Erythroid differentiation; FBS; Hb; Bile acid derivatives; GAPDH; HPLC; PCR; Platinum complexes; Steroid; Divalent metal Complexes; Sickle cell anemia; Hydroxycarbamide; Erythroid cell; Tertiary phosphine; Ligand; Leukemia; Phosphorus Organic compounds; Blood; Messenger RNA; Bile acid; Production; Hemoglobin; Fetus; Chemical synthesis; Tumor cell; Platinum II Complexes; Human; Cholane derivatives; Precursor cell; Patient; Malignant hemopathy; Transition metal Complexes; Ammino complex; Cell differentiation; In vitro; Biological activity; Cisplatin; Protein; Genetic disease; In vivo; Alkylating agent; Cell line; Carboxylate
• ISSN: 0968-0896; 1464-3391
• DOI: 10.1016/j.bmc.2006.04.003

Several bile acid derivatives and their platinum(II) bonded forms were tested as potential inducers of erythroid differentiation of human leukemic K562 cells. cis-[(3-Dehydrocholanoyliden- l-tartrate)-diammineplatinum(II)] stimulates erythroid differentiation of K562 cells and an increase of fetal hemoglobin (HbF) production in erythroid precursor cells from peripheral blood. In this study, we compared some bile acid derivatives and their platinum(II) complexes with respect to their ability to induce erythroid differentiation of human leukemic K562 cells. The complexes analyzed were cis-[(3-dehydrocholanoyliden- l-tartrate)-diammineplatinum(II)] (compound 1) and cis-[di(dehydrocholanoate)-bis(triphenylphosphine)-platinum(II)] (compound 3), together with their free ligands, respectively, 3-dehydrocholanoyliden- l-tartaric acid (compound 2) and dehydrocholanoic acid ( 4), and their parent compounds, respectively, cisplatin and cis-[dichloride-bis(triphenylphosphine)-platinum(II)] ( 5). We found that compound 1 stimulates erythroid differentiation of K562 cells and an increase of fetal hemoglobin (HbF) production in erythroid precursor cells isolated from peripheral blood of human subjects. This increase is similar to that obtained by hydroxyurea, a potent inducer of HbF production both in vitro and in vivo. Another important conclusion of this study is related to the evaluation of the effects of compound 1 on production of γ-globin mRNA in human erythroid precursors grown in the two-stage liquid culture system. We demonstrated that compound 1 induces preferential accumulation of γ-globin mRNA. The results presented in this manuscript could have practical impact, since it is well known that an increase in HbF production could ameliorate the clinical status of patients with β-thalassemia and sickle cell anemia.