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Platinum(IV) Derivatives of [Pt(1S,2S-diaminocyclohexane)(5,6-dimethyl-1,10-phenanthroline)] with Diclofenac Ligands in the Axial Positions: A New Class of Potent Multi-action Agents Exhibiting Selectivity to Cancer Cells
H. Kostrhunova, BS. McGhie, L. Markova, O. Novakova, J. Kasparkova, JR. Aldrich-Wright, V. Brabec
Jazyk angličtina Země Spojené státy americké
Typ dokumentu časopisecké články, práce podpořená grantem
- MeSH
- antiflogistika nesteroidní farmakologie MeSH
- diklofenak farmakologie MeSH
- ligandy MeSH
- nádorové buněčné linie MeSH
- nádory * MeSH
- organoplatinové sloučeniny farmakologie MeSH
- platina MeSH
- prekurzory léčiv * MeSH
- protinádorové látky * MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
The platinum(II) complex [Pt(1S,2S-diaminocyclohexane)(5,6-dimethyl-1,10-phenanthroline)]2+ (PtII56MeSS, 1) exhibits high potency across numerous cancer cell lines acting by a multimodal mechanism. However, 1 also displays side toxicity and in vivo activity; all details of its mechanism of action are not entirely clear. Here, we describe the synthesis and biological properties of new platinum(IV) prodrugs that combine 1 with one or two axially coordinated molecules of diclofenac (DCF), a non-steroidal anti-inflammatory cancer-selective drug. The results suggest that these Pt(IV) complexes exhibit mechanisms of action typical for Pt(II) complex 1 and DCF, simultaneously. The presence of DCF ligand(s) in the Pt(IV) complexes promotes the antiproliferative activity and selectivity of 1 by inhibiting lactate transporters, resulting in blockage of the glycolytic process and impairment of mitochondrial potential. Additionally, the investigated Pt(IV) complexes selectively induce cell death in cancer cells, and the Pt(IV) complexes containing DCF ligands induce hallmarks of immunogenic cell death in cancer cells.
Institute of Biophysics Czech Academy of Sciences Kralovopolska 135 CZ 61200 Brno Czech Republic
School of Science Western Sydney University Penrith South DC 1797 New South Wales Australia
Citace poskytuje Crossref.org
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- $a Kostrhunova, Hana $u Institute of Biophysics, Czech Academy of Sciences, Kralovopolska 135, CZ-61200 Brno, Czech Republic
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- $a The platinum(II) complex [Pt(1S,2S-diaminocyclohexane)(5,6-dimethyl-1,10-phenanthroline)]2+ (PtII56MeSS, 1) exhibits high potency across numerous cancer cell lines acting by a multimodal mechanism. However, 1 also displays side toxicity and in vivo activity; all details of its mechanism of action are not entirely clear. Here, we describe the synthesis and biological properties of new platinum(IV) prodrugs that combine 1 with one or two axially coordinated molecules of diclofenac (DCF), a non-steroidal anti-inflammatory cancer-selective drug. The results suggest that these Pt(IV) complexes exhibit mechanisms of action typical for Pt(II) complex 1 and DCF, simultaneously. The presence of DCF ligand(s) in the Pt(IV) complexes promotes the antiproliferative activity and selectivity of 1 by inhibiting lactate transporters, resulting in blockage of the glycolytic process and impairment of mitochondrial potential. Additionally, the investigated Pt(IV) complexes selectively induce cell death in cancer cells, and the Pt(IV) complexes containing DCF ligands induce hallmarks of immunogenic cell death in cancer cells.
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