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

Our plain-English summary of Platinum-bisphosphonate complexes have proven to be inactive chemotherapeutics targeted for malignant mesothelioma because of inappropriate hydrolysis, by N. Margiotta, R. Ostuni, S. Piccinonna, et al (Journal of Inorganic Biochemistry, 2011).

The study

• Authors: N. Margiotta, R. Ostuni, S. Piccinonna, G. Natile, I. Zanellato, C.D. Boidi, I. Bonarrigo, D. Osella
• Journal: Journal of Inorganic Biochemistry
• Published: 2011;105(4):548-57
• Cited by: 12 articles, as counted by NIH iCite
• Read it: PubMed · Publisher

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.

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In plain English

This was a laboratory chemistry and cell-culture study. It did not study people or asbestos exposure. The authors made new compounds that join platinum, which is used in standard mesothelioma chemotherapy, to nitrogen-containing bisphosphonates. These are bone drugs that the authors describe as collecting in pleural mesothelioma. They tested the compounds on two cell lines grown from the pleural fluid of untreated patients with malignant pleural mesothelioma: BR95 (epithelioid type) and MM98 (sarcomatoid type). The joined compounds showed only modest activity against the cells. When compared with their separate building blocks, two of the compounds (1b and 2b) showed an antagonistic effect, meaning the parts worked against each other. Free bisphosphonates block a particular cell pathway, but the joined compounds did not. Cells also generally took up less platinum from compound 2b than from a simpler platinum model compound. In solutions mimicking body conditions, the compounds did not break apart into their two active parts. The authors concluded that this slow, inadequate breakdown explained the results, and they planned redesigned compounds.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: Laboratory study: chemical synthesis of new platinum-bisphosphonate compounds, plus in vitro (cell culture) testing
• Who was studied: Two primary malignant pleural mesothelioma cell lines derived from the pleural effusion of previously untreated patients: BR95 (epithelioid phenotype) and MM98 (sarcomatoid phenotype). No patients were studied directly.
• Exposure: No asbestos exposure was studied. The cells were treated with experimental drug compounds: dinuclear platinum complexes bridged by nitrogen-containing bisphosphonates (1a–3b), free nitrogen-containing bisphosphonates, and platinum-malonate model complexes, with cisplatin and carboplatin as comparisons.
• Main results:
  • The MM98 (sarcomatoid) cells were somewhat more sensitive to the compounds tested than the BR95 (epithelioid) cells; the reverse was true for cisplatin and carboplatin.
  • Against MM98 cells, the compounds carrying the cis-1,4-DACH ligand (1b–3b) were far more active than those carrying ammine ligands (1a–3a).
  • Based on combination index values, compounds 1b and 2b behaved antagonistically compared with their separate building blocks (model compound 4b and free bisphosphonate).
  • Unlike the free bisphosphonates 1 and 2, model compound 4b and compounds 1b–3b showed no sign of blocking the mevalonate pathway in either cell line.
  • Platinum uptake by cells was generally greater for model compound 4b than for 2b, and greater in MM98 than in BR95 cells. Free bisphosphonate 2 did not change the uptake of 4b.
  • In physiological-like solution, compound 1b did not release free bisphosphonate or active [PtCl2(cis-1,4-DACH)] after 72 h. For compound 2b, a new species accounted for nearly 25% of the total phosphorus after 72 h, and no free pamidronate was detected.
• The authors' conclusion: The authors concluded that the platinum-bisphosphonate complexes showed modest activity. They concluded that the two building blocks do not act independently once the compound reaches its target, because the compounds break down slowly and inadequately. They planned modified compounds with a hydrolysable spacer.
• Limitations the authors state:
  • The authors stated that full characterization of the new species formed when compound 1b broke down was beyond the scope of the paper; their proposed structures were based on NMR data.
  • The combination index analysis could not be done for compound 3b, because free bisphosphonate 3 was inactive across the concentrations tested.

Topics

The National Library of Medicine indexes this study under subjects our site covers: Mesothelioma.

Medical terms in this study, explained in our Lexicon: Malignant Mesothelioma, Pleural Mesothelioma, Mesothelioma.

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