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Cisplatin and beyond: molecular mechanisms of action and drug resistance development in cancer chemotherapy

Tomaz Makovec

Tomaz Makovec

Institute of Biochemistry, Faculty of Medicine, University of LjubljanaLjubljana, Slovenia
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Makovec, Tomaz
  
28. März 2019
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Artikel-Kategorie: Review
Online veröffentlicht: 28. März 2019
Seitenbereich: 148 - 158
Eingereicht: 20. Juli 2018
Akzeptiert: 05. Sept. 2018
DOI: https://doi.org/10.2478/raon-2019-0018
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© 2019 Tomaz Makovec, published by Sciendo
This work is licensed under the Creative Commons Attribution-NonCommercial-NoDerivatives 3.0 License.

Figure 1

The behaviour of cisplatin in aqueous solution. Cisplatin (1) is a bright-yellow solid; when dissolved in water it is attacked by water molecules and as a result one of the chloride ions is eliminated and monoaqua (2) species is formed. Diaqua species (3) is formed when the second water molecule replaces the chloride ion. Water replaces chloride ions because the metal and nitrogen form stronger bond than metal and the chloride ion. Bound water became very acidic and at physiologic pH became completely deprotonated – as a monohydroxo form (4), and the product of the dissociation of the second proton from the diaqua form is dihydroxo species (6). Logarithms of rate constants (pK1, pK-1, pK2 and pK-2) are given for 25 ºC and of dissociation constants (pKa1, pKa2 and pKa3) for 27 ºC.
The behaviour of cisplatin in aqueous solution. Cisplatin (1) is a bright-yellow solid; when dissolved in water it is attacked by water molecules and as a result one of the chloride ions is eliminated and monoaqua (2) species is formed. Diaqua species (3) is formed when the second water molecule replaces the chloride ion. Water replaces chloride ions because the metal and nitrogen form stronger bond than metal and the chloride ion. Bound water became very acidic and at physiologic pH became completely deprotonated – as a monohydroxo form (4), and the product of the dissociation of the second proton from the diaqua form is dihydroxo species (6). Logarithms of rate constants (pK1, pK-1, pK2 and pK-2) are given for 25 ºC and of dissociation constants (pKa1, pKa2 and pKa3) for 27 ºC.

Figure 2

Traffic of cisplatin (CP). 1, passive diffusion, 2, passive diffusion blocked. See text for explanations. CP: cisplatin, DACP: diaqua cisplatin, OCT: organic cation transporter, OAT: organic anion transporter, Ctr: copper transporter, MRP: multidrug resistance-associated protein, ATP7: copper-transporting P-type ATPase, MATE: multidrug extrusion transporter, GSH: glutathione, MT: metallothionein.
Traffic of cisplatin (CP). 1, passive diffusion, 2, passive diffusion blocked. See text for explanations. CP: cisplatin, DACP: diaqua cisplatin, OCT: organic cation transporter, OAT: organic anion transporter, Ctr: copper transporter, MRP: multidrug resistance-associated protein, ATP7: copper-transporting P-type ATPase, MATE: multidrug extrusion transporter, GSH: glutathione, MT: metallothionein.

Polymorphisms of transporters that influence the efficacy of platinum drugs

ProteinGeneGenetic polymorphisms or expression level (EL) that influences the outcome of platinum-based therapy
Uptake of platinum drugs
OCT1SLC22A1c.181C > T, c.480C > G, c.1022C > T, c.1222A > G, c.1390G > A, c.1463G > T
OCT2SLC22A2c.160C > T, c.481 T > C, c.493A > G, c.495G > A, c.808G > T, c.890C > G, c.1198C > T, c.1294A > C
OCT3SLC22A3EL
CTR1SLC31A1rs10981694 A>C
CTR2SLC31A2

Polymorphisms of DNA-platinum drug adducts repairing enzymes

ProteinGenePolymorphisms
DNA-adduct repair system
ERCC1ERCC1c.8092C>A, c.C354T
XRCC1XRCC1c.C580T, c.A1196G
XRCC3XRCC2p.Thr241Met, c.C241T
XPDXPDp.Lys751Gln, c.A2251C, c.C2133T
XPGc.T242C
XPA5’UTR
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