Water soluble cationic trans-platinum complexes which induce programmed cell death in the protozoan parasite Leishmania infantum

• Published in: Journal of inorganic biochemistry 2005-03, Vol.99 (3), p.727-736
• Main Authors: Nguewa, Paul A., Fuertes, Miguel A., Iborra, Salvador, Najajreh, Yousef, Gibson, Dani, Martínez, Enrique, Alonso, Carlos, Pérez, José M.
• Format: Article
• Language: English
• Subjects: Amino Acid Sequence; Animals; Annexin-V/PI flow cytometry; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; Apoptosis - drug effects; Binding Sites; Butylamines - chemistry; Butylamines - pharmacology; Cations; CD and fluorescence spectroscopies; Cisplatin - chemistry; Cisplatin - pharmacology; DNA - chemistry; DNA and Ub conformational changes; Leishmania infantum - drug effects; Leishmania infantum - metabolism; Molecular Sequence Data; Picolines - chemistry; Picolines - pharmacology; Piperazines - chemistry; Piperazines - pharmacology; Piperidines - chemistry; Piperidines - pharmacology; Platinum Compounds - chemistry; Platinum Compounds - pharmacology; Programmed cell death; Stereoisomerism; Structure-Activity Relationship; Trans-platinum antileishmanial drugs; Tumor Cells, Cultured; Ubiquitin - chemistry; Water - chemistry
• ISSN: 0162-0134; 1873-3344
• DOI: 10.1016/j.jinorgbio.2004.12.008

We have evaluated the cytotoxic properties against the protozoan Leishmania infantum of four water soluble cationic trans-Pt(II)Cl 2 compounds containing as inert groups NH 3 and piperazine ( 1), 4-picoline and piperazine ( 2), n-butylamine and piperazine ( 3), and NH 3 and 4-piperidino-piperidine ( 4). The leishmanicidal activity of compounds 3 and 4 against promastigotes of the parasite Leishmania infantum was 2.5- and 1.6-times higher than that of the cytotoxic drug cis-diamminedichloroplatinum(II), respectively. Interestingly, compounds 3 and 4 produce in Leishmania infantum promastigotes a higher amount of programmed cell death than cisplatin, which is associated with cell cycle arrest in G2/M. In contrast to cis-diamminedichloroplatinum(II), binding of compounds 3 and 4 to calf thymus DNA induces conformational changes more similar to those of trans-diamminedichloroplatinum(II) that may be attributed to denaturation of the double helix. Similarly to cis-diamminedichloroplatinum(II) and trans-diamminedichloroplatinum(II), the interaction of compounds 3 and 4 with ubiquitin results in an increase of the α-helix content of the protein as observed by circular dichroism spectroscopy. However, fluorescence studies indicate that compounds 3 and 4 produce a decrease in the fluorescence of the tyrosine 59 residue of ubiquitin higher than both cis-diamminedichloroplatinum(II) and trans-diamminedichloroplatinum(II). Altogether, our results suggest that the biochemical mechanism of cytotoxic activity of compounds 3 and 4 against Leishmania infantum must be different from that of cis-diamminedichloroplatinum(II). To the best of our knowledge, compounds 3 and 4 are the first reported trans-platinum complexes that show antiparasitic activity.