Triple action Pt(<scp>iv</scp>) derivatives of cisplatin: a new class of potent anticancer agents that overcome resistance

Petruzzella, Emanuele; Sirota, Roman; Solazzo, Irene; Gandin, Valentina; Gibson, Dan

doi:10.1039/c8sc00428e

Cited by 130 publications

(116 citation statements)

References 42 publications

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“…The 195 Pt NMR chemical shifts are determined by the oxidation state of the Pt as well as by the ligands in the first coordination sphere. The signal at approximately 1050 ppm is consistent with the formation of a monocarboxylated derivative of oxoplatin, and the shift to about 1150 ppm is consistent with the formation of a dicarboxylated compound . The product was isolated by preparative HPLC (C18 RP column, 0–90 % linear gradient of acetonitrile over 30 min, retention time=27.5 min), and finally lyophilized.…”

Section: Resultsmentioning

confidence: 99%

An Anticancer Pt^IV Prodrug That Acts by Mechanisms Involving DNA Damage and Different Epigenetic Effects

Kostrhunová

Petruzzella

Gibson

et al. 2019

Chemistry A European J

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Dual‐ or multi‐action PtIV prodrugs represent a new generation of platinum anticancer drugs. The important property of these PtIV prodrugs is that their antitumor action combines several different mechanisms owing to the presence of biologically active axial ligands. This work describes the synthesis and some biological properties of a “triple‐action” prodrug that releases in cancer cells cisplatin and two different epigenetically acting moieties, octanoate and phenylbutyrate. It is demonstrated, with the aid of modern methods of molecular and cellular biology and pharmacology, that the presence of three different functionalities in a single molecule of the PtIV prodrug results in a selective and high potency in tumor cells including those resistant to cisplatin [the IC50 values in the screened malignant cell lines ranged from as low as 9 nm (HCT‐116) to 74 nm (MDA‐MB‐231)]. It is also demonstrated that cellular activation of the PtIV prodrug results in covalent modification of DNA through the release of the platinum moiety accompanied by inhibition of the activity of histone deacetylases caused by phenylbutyrate and by global hypermethylation of DNA by octanoate. Thus, the PtIV prodrug introduced in this study acts as a true “multi‐action” prodrug, which is over two orders of magnitude more active than clinically used cisplatin, in both 2D monolayer culture and 3D spheroid cancer cells.

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Section: Resultsmentioning

confidence: 99%

An Anticancer Pt^IV Prodrug That Acts by Mechanisms Involving DNA Damage and Different Epigenetic Effects

Kostrhunová

Petruzzella

Gibson

et al. 2019

Chemistry A European J

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“…The combination of NSAIDs with Pt (II) drugs in the form of a single Pt (IV) prodrug to increase the efficiency and reduce side‐effects of chemotherapy can be an attractive strategy to treat a variety of cancer tumors. Pt (IV) compounds that have been investigated in this context include complexes with ibuprofen and indomethacin as the axial ligands . The Pt (IV) derivative of cisplatin with one axial aspirin and one hydroxido ligand was shown to exhibit a potent cytotoxic activity and anti‐inflammatory properties …”

Section: Introductionmentioning

confidence: 99%

Anti‐tumor platinum (IV) complexes bearing the anti‐inflammatory drug naproxen in the axial position

Tolan

Abdel‐Monem

El-Nagar

2019

Applied Organom Chemis

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The role of inflammation in cancer generation is gaining importance in the field of cancer research. The chemo‐anti‐inflammatory strategy that involves using non‐steroidal anti‐inflammatory drug compounds as effective anti‐tumor agents is being acceded globally. In the present study, seven new Pt (IV) complexes based on cisplatin, carboplatin and oxaliplatin scaffold bearing the anti‐inflammatory drug naproxen in the axial position were synthesized and characterized by elemental analysis, ESI‐MS, Fourier transform‐infrared, 1H‐ and 195Pt‐NMR spectroscopy. The reduction behavior in the presence of ascorbic acid was studied using high‐performance liquid chromatography. The cytotoxicity against two human breast cell lines and the anti‐inflammatory properties were evaluated. All the complexes are able to promote a comparable activity, with average three‐ and 13‐fold more cytotoxic than cisplatin against MCF7 and MDA‐MB‐231 cell lines, respectively. The complexes show remarkable anti‐inflammatory effects, which indicated their potential in treating cancer associated with inflammation and reducing side‐effects of chemotherapy.

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“…To monitor the in vitro anticancer potency of the title compounds against cisplatin‐resistant cells, the IC 50 values were also evaluated in cisplatin‐resistant ovarian cancer cell line (A2780‐CisR), and the resistance factor (RF) was measured from the ratio of the IC 50 values for the resistant and wild‐type cell lines. As we can see, the effect of cisplatin is quite negligible on A2780‐CisR, yielding an RF value of 9.3 . However, the cytotoxic potency of complex 1 and the nanocarrier is higher than cisplatin, by a factor of about 2, with an RF value of 1.4 for complex 1 and 4.6 for nanocarrier.…”

Section: Resultsmentioning

confidence: 82%

“…As we can see, the effect of cisplatin is quite negligible on A2780-CisR, yielding an RF value of 9.3. [41] However, the cytotoxic potency of complex 1 and the nanocarrier is higher than cisplatin, by a factor of about 2, with an RF value of 1.4 for complex 1 and 4.6 for nanocarrier.…”

Section: Antitumor Evaluationmentioning

confidence: 99%

Improvement of the Biological Activity of a New Cobalt(III) Complex through Loading into a Nanocarrier, and the Characterization Thereof

et al. 2019

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In an effort to use a polymer carrier for the maintenance of biological activity of metal complexes; in this report, a novel cobalt(III) complex, trans‐[Co(en)2(mtzt)2]NO3 (1) was prepared (en=ethylenediamine and Hmtzt=1‐methyl‐1‐H‐1,2,3,4‐tetrazol‐5‐thiol) and fully characterized. A biocompatible di‐block polymer, containing poly lactic‐co‐glycolic acid and poly ethylene glycol (PLGA‐PEG), was employed as the nanocarrier of complex 1 to achieve more efficacy and controlled drug release. Results illustrated that the successful loading of the cobalt complex on the PLGA‐PEG polymer as well as pH dependent drug release with approximately 17%, 58% and 74% release within 168 hours at pH=7.4, 5.8 and 4.8 respectively. Antibacterial properties of complex 1 and corresponding nanocarrier have been determined against gram‐negative (Escherichia coli) and gram‐positive (Staphylococcus aureus) bacteria where the loading of the complex on nanocarrier enhances its antibacterial activity. Their anticancer activity was also evaluated over human ovarian carcinoma cells and compared with cisplatin.

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Triple action Pt(iv) derivatives of cisplatin: a new class of potent anticancer agents that overcome resistance

Abstract: A series of triple action Pt(iv) prodrugs was designed to test the hypothesis that multi-action compounds, where each bioactive moiety intervenes in several cellular processes, might be more effective than a single agent at killing cancer cells.

Cited by 130 publications

References 42 publications

An Anticancer Pt^IV Prodrug That Acts by Mechanisms Involving DNA Damage and Different Epigenetic Effects

An Anticancer Pt^IV Prodrug That Acts by Mechanisms Involving DNA Damage and Different Epigenetic Effects

Anti‐tumor platinum (IV) complexes bearing the anti‐inflammatory drug naproxen in the axial position

Improvement of the Biological Activity of a New Cobalt(III) Complex through Loading into a Nanocarrier, and the Characterization Thereof

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Triple action Pt(iv) derivatives of cisplatin: a new class of potent anticancer agents that overcome resistance

Abstract: A series of triple action Pt(iv) prodrugs was designed to test the hypothesis that multi-action compounds, where each bioactive moiety intervenes in several cellular processes, might be more effective than a single agent at killing cancer cells.

Cited by 130 publications

References 42 publications

An Anticancer PtIV Prodrug That Acts by Mechanisms Involving DNA Damage and Different Epigenetic Effects

An Anticancer PtIV Prodrug That Acts by Mechanisms Involving DNA Damage and Different Epigenetic Effects

Anti‐tumor platinum (IV) complexes bearing the anti‐inflammatory drug naproxen in the axial position

Improvement of the Biological Activity of a New Cobalt(III) Complex through Loading into a Nanocarrier, and the Characterization Thereof

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An Anticancer Pt^IV Prodrug That Acts by Mechanisms Involving DNA Damage and Different Epigenetic Effects

An Anticancer Pt^IV Prodrug That Acts by Mechanisms Involving DNA Damage and Different Epigenetic Effects