TY - JOUR
T1 - Platinum-bisphosphonate complexes have proven to be inactive chemotherapeutics targeted for malignant mesothelioma because of inappropriate hydrolysis
AU - Margiotta, Nicola
AU - Ostuni, Rosa
AU - Piccinonna, Sara
AU - Natile, Giovanni
AU - Zanellato, Ilaria
AU - Boidi, Carla Doriana
AU - Bonarrigo, Ilaria
AU - Osella, Domenico
PY - 2011/4
Y1 - 2011/4
N2 - 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.
AB - 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.
KW - Bifunctional drug candidates
KW - Bisphosphonates
KW - Drug targeting and delivery
KW - Malignant mesothelioma
KW - Platinum complexes
UR - http://www.scopus.com/inward/record.url?scp=79951568460&partnerID=8YFLogxK
U2 - 10.1016/j.jinorgbio.2010.12.011
DO - 10.1016/j.jinorgbio.2010.12.011
M3 - Article
SN - 0162-0134
VL - 105
SP - 548
EP - 557
JO - Journal of Inorganic Biochemistry
JF - Journal of Inorganic Biochemistry
IS - 4
ER -