title: Platinum-bisphosphonate complexes have proven to be inactive chemotherapeutics targeted for malignant mesothelioma because of inappropriate hydrolysis.
abstract: Bisphosphonates (BPs), the synthetic analogues of pyrophosphate, are widely used in the treatment of metabolic bone diseases. BPs exhibit a preferential accumulation in malignant pleural mesothelioma (MPM) and, furthermore, nitrogen-containing BPs (n-BPs) show significant inhibition of MPM cell proliferation. We synthesised dinuclear platinum(II) complexes containing a n-BP moiety as bridging ligand and am(m)ines as terminal ligands (Pt-n-BP)s, with the aim of obtaining bifunctional mesothelioma-targeted drugs. We compared the antiproliferative effect of the single drugs (i.e. Pt-model and n-BPs) with that of the preformed Pt-n-BP complexes by means of the combination index (CI) in order to assess the synergistic/additive/antagonistic effect of the two constituents in the resulting conjugates. The combination of the two individual drugs was almost additive, while the preformed Pt-n-BP produced an antagonistic effect. Furthermore, (Pt-n-BP)s neither inhibited the mevalonate pathway (as n-BPs normally do) nor increased the Pt uptake. The minimal biological results of these conjugates could be traced back to a slow and inappropriate hydrolysis, that does not split the adduct into active components.
authors.affiliation: Dipartimento Farmaco-Chimico, Università di Bari A. Moro, Via E. Orabona 4, Bari, Italy.
authors.forename: Nicola
authors.initials: N
authors.lastname: Margiotta
authors.forename: Rosa
authors.initials: R
authors.lastname: Ostuni
authors.forename: Sara
authors.initials: S
authors.lastname: Piccinonna
authors.forename: Giovanni
authors.initials: G
authors.lastname: Natile
authors.forename: Ilaria
authors.initials: I
authors.lastname: Zanellato
authors.forename: Carla Doriana
authors.initials: CD
authors.lastname: Boidi
authors.forename: Ilaria
authors.initials: I
authors.lastname: Bonarrigo
authors.forename: Domenico
authors.initials: D
authors.lastname: Osella
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000627:therapeutic use; D045744:Cell Line, Tumor; D004164:Diphosphonates / Q000138:chemical synthesis / Q000737:chemistry* / Q000627:therapeutic use; D006801:Humans; D006868:Hydrolysis; D008024:Ligands; D008654:Mesothelioma / Q000188:drug therapy*; D010984:Platinum / Q000737:chemistry* / Q000627:therapeutic use; D021241:Spectrometry, Mass, Electrospray Ionization
chemical_list: D000970:Antineoplastic Agents; D004164:Diphosphonates; D008024:Ligands; D010984:Platinum