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

doi:10.1016/j.bmc.2006.04.003

Bioorganic & Medicinal Chemistry

Volume 14, Issue 15, 1 August 2006, Pages 5204-5210

https://doi.org/10.1016/j.bmc.2006.04.003 Get rights and content

Abstract

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.

Graphical abstract

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.

Introduction

The search of potential therapeutic agents for β-thalassemia and sickle cell anemia focuses on the pharmacologically mediated regulation of the expression of human γ-globin genes.1, 2, 3, 4, 5, 6, 7, 8 It is well established that an increase of production of fetal hemoglobin (HbF, α₂γ₂) leads to a significant improvement of the clinical status of the patients.4, 5, 7 Therefore, many recently published experiments were designed to find hormones, cytotoxic agents, hemopoietic cytokines, and short fatty acids as agents able to increase HbF levels in humans.1, 2, 3, 9, 10

In this respect, platinum complexes are of great interest. We demonstrated and published that cisplatin is a potent inducer of HbF production in human erythroid cells.¹¹ These data have been recently supported by the results obtained after in vitro treatment with these compounds of cells harboring a GFP construct under the control of the human γ-globin promoter.¹²

However, cisplatin and related compounds exhibit a high level of cytoxicity in vitro and in vivo. Therefore, they might be proposed for ‘acute’ treatments (such as in the case of patients affected by tumors), being of low priority in the chronic treatment of disorders, such as thalassemia, for which recurrent administrations are expected to be required for several years. Therefore, ligands for platinum complexes able to alter the pharmacokinetics might be of interest. These should maintain however the cisplatin-mediated effect inside the cell.

Looking for anticancer platinum complexes with alternative biodistribution to cisplatin, we have recently screened the antiproliferative activity of a large group of Pt-complexes bearing bile acids or bile acid derivatives as carrier ligands with special properties like amphiphilicity and organotropism towards the hepatobiliary system.13, 14 We found that the most active species were the amino–Pt complex 1 and the triphenylphosphine–Pt complex 3.¹⁵ While amino–platinum complexes (cisplatin and its various analogues) have been considered and largely used as anticancer drugs, the use of lipophilic triphenylphosphine as ligand for platinum is still controversial, although it appears in some metal-complexes with diagnostic or therapeutic applications.¹⁶

In the present study, we report the biological characterization of 1 and 3 (in parallel with their carrier ligands and their parent compounds) with respect to: (a) induction of differentiation of human erythroleukemia cells and (b) possible induction of HbF in erythroid precursor cells.

These compounds were therefore investigated for potential erythro-differentiation ability, in order to verify whether some of them could be able to increase γ-globin gene expression. First, we analyzed erythroid differentiation by benzidine/H₂O₂ assay using as cellular model the human leukemia K562 cell line.17, 18 Second, we analyzed γ-globin mRNA and HbF production after in vitro treatment of erythroid precursor cells using the two-phase liquid culture procedure.19, 20 This methodology can be used to identify compounds stimulating HbF accumulation in erythroid progenitors obtained from normal donors as well as subjects with hematological disorders.²¹

Section snippets

Evaluation of erythroid differentiation and antiproliferative effects on K562 cell line after treatment with platinum(II) bonded forms of synthetic bile acid derivatives

Figure 1 shows the molecular structures of the employed platinum complexes cis-[(3-dehydrocholanoyliden-l-tartrate)-diammineplatinum(II)] (compound 1) and cis-[di(dehydrocholanoate)-bis(triphenylphosphine)-platinum(II)] (compound 3), their carrier ligands 3-dehydrocholanoyliden-l-tartaric acid (compound 2) and dehydrocholanoic acid (4), and their parent compounds, cisplatin and cis-[dichloride-bis(triphenylphosphine)-platinum(II)] (5).

The antiproliferative effects of compounds 1–5 and cisplatin

Discussion

HbF inducers could be of great interest for therapy of β-thalassemia and sickle cell anemia,1, 2, 3, 4, 5, 6, 7, 8 since an increase of HbF is able to ameliorate the symptoms of these diseases.

We report in this paper that a platinum(II) bonded form of a synthetic bile acid derivative (compound 1) is a potent inducer of erythroid differentiation of K562 cells.

The K562 cell line has been proposed as a useful in vitro model for studying the molecular mechanism(s) regulating the expression of

Chemistry

All the solvents were distilled according to standard methods and other chemicals were used as purchased (reagent grade). Dehydrocholanoic acid (4) was supplied by I.C.E., cisplatin and cis-[dichloride-bis(triphenylphosphine)-platinum(II)] were prepared following literature procedures.37, 38 Elemental analyses (C, H, and N) were performed using a Carlo Erba instrument model EA1110. FT-IR spectra were recorded on a Nicolet 510 P FT-IR instrument (4000–200 cm⁻¹) using KBr. NMR spectra were recorded

Acknowledgments

We thank I.C.E. S.r.l. (Industria Chimica Emiliana) for supplying the products described in this paper. We thank Pharmacia & Upjohn and Ministero Università e Ricerca Scientifica (MURST) (60%) for generous financial support of this work. R.G. is granted by AIRC, Cofin-2002 and by Fondazionl CARIPARO. This research is also supported by Regione Emilia-Romagna (Spinner Project), by Associazione Veneta per la Lotta alla Talassemia (AVLT), and by Consorzio Interuniversitario di Ricerca in Chimica

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

Abstract

Graphical abstract

Introduction

Section snippets

Evaluation of erythroid differentiation and antiproliferative effects on K562 cell line after treatment with platinum(II) bonded forms of synthetic bile acid derivatives

Discussion

Chemistry

Acknowledgments

Blood

Blood Rev.

Blood

Curr. Opin. Genet. Dev.

Biochem. Pharmacol.

J. Hepatol.

Cell Differ.

Blood

Blood

Exp. Hematol.

Blood

J. Inorg. Nucl. Chem.

N. Eng. J. Med.

N. Eng. J. Med.

Br. J. Haematol.

Ann. N.Y. Acad. Sci.

Eur. J. Haematol.

Exp. Hematol.

Hum. Mol. Genet.