Platinum-bisphosphonate complexes have proven to be inactive chemotherapeutics targeted for malignant mesothelioma because of inappropriate hydrolysis

Nicola Margiotta, Rosa Ostuni, Sara Piccinonna, Giovanni Natile, Ilaria Zanellato, Carla Doriana Boidi, Ilaria Bonarrigo, Domenico Osella

Risultato della ricerca: Contributo su rivistaArticolo in rivistapeer review

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.

Lingua originaleInglese
pagine (da-a)548-557
Numero di pagine10
RivistaJournal of Inorganic Biochemistry
Volume105
Numero di pubblicazione4
DOI
Stato di pubblicazionePubblicato - apr 2011
Pubblicato esternamente

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