Cellular accumulation and DNA interaction studies of cytotoxic trans-platinum anticancer compounds

Abstract

Forty years after the discovery of the anticancer effects of cisplatin, scientists are still pursuing the development of platinum complexes with improved properties regarding side effects and resistance, which are two main problems in cisplatin treatment. Among these compounds, trans-configured platinum complexes with oxime ligands emerged as a new class with features distinct from those of established anticancer agents, including different DNA binding behavior, increased cellular accumulation, and a different pattern of protein interaction. We report herein on the reactivity with biomolecules of three novel pairs of cis- and trans-configured acetone oxime platinum(II) complexes and one pair of 3-pentanone oxime platinum(II) complexes. Cellular accumulation experiments and in vitro DNA platination studies were performed and platinum contents were determined by inductively coupled plasma mass spectrometry. The trans-configured complexes were accumulated in SW480 cells in up to 100 times higher amounts than cisplatin and up to 50 times higher amounts than their cis-configured counterparts; r (b) values (number of platinum atoms per nucleotide) were more than tenfold increased in cells treated with trans complexes compared with cells treated with cisplatin. The interaction of the complexes with DNA was studied in cell-free experiments with plasmid DNA (pUC19), in capillary zone electrophoresis with the DNA model 2-deoxyguanosine 5'-monophosphate, and in in vitro experiments showing the degree of DNA damage in the comet assay. Whereas incubation with cis compounds did not induce degradation of DNA, the trans complexes led to pronounced strand cleavage.

Small-Molecule Bcl2 BH4 Antagonist for Lung Cancer Therapy

“…To test whether BDA-366 reacts with DNA as a crosslinker, electrophoretic mobility shift assay (EMSA) was performed as described (Bartel et al, 2012). Cisplatin, a known DNA binding agent, was used as positive control.…”

Crystal structure and antimicrobial activity of a transplatin adduct of N,N′-dimethylthiourea, trans-[Pt(NH3)2(dmtu)2]Cl2

“…The main target site of platinum is DNA and the major adducts formed by these compounds are 1,2-intrastrand cross-links involving guanine and adenine bases [1][2][3][4][5][6][7][8][9][10]. Trans-Diamminedichloridoplatinum(II) (transplatin) on the other hand was found to be inactive against cancer cells due to its inability to form 1,2-intrastrand cross-links because of steric constraints [1][2][3][4][5][6][7][8][9][10][11]. However, several transplatin analogues composed of iminoethers, aliphatic amines, and heterocyclic ligands are known to exhibit cytotoxic effects in a number of tumor cell lines including those resistant to cisplatin [11][12][13][14][15][16].…”

“…Trans-Diamminedichloridoplatinum(II) (transplatin) on the other hand was found to be inactive against cancer cells due to its inability to form 1,2-intrastrand cross-links because of steric constraints [1][2][3][4][5][6][7][8][9][10][11]. However, several transplatin analogues composed of iminoethers, aliphatic amines, and heterocyclic ligands are known to exhibit cytotoxic effects in a number of tumor cell lines including those resistant to cisplatin [11][12][13][14][15][16]. Trans compounds mainly form N7-guanine monofunctional adducts [2,8,10,17] and interstrand cross-links between the N7-nitrogen of guanine and the N3-nitrogen of its basepaired cytosine [2,8,10,18].…”

“…In contrast to cisplatin-DNA conjugates, transplatin-DNA adducts are not recognized by those proteins, making them susceptible to repair [10][11][12][13]. The cytotoxic activity of some trans-platinum complexes in cisplatin-resistant cell lines and their different DNAbinding behavior suggest a different mode of action for these compounds [11].…”

Phosphorus–nitrogen compounds: part 30. Syntheses and structural investigations, antimicrobial and cytotoxic activities and DNA interactions of vanillinato-substituted NN or NO spirocyclic monoferrocenyl cyclotriphosphazenes

“…The concentrations (in μM) are as follows: lane 1 untreated plasmid DNA (lane 2-6 compound treated DNA) lane 2 2,500, lane 3 1,250; lane 4 625; lane 5 312; lane 6 125 the DNA causes a retardation of the fast running band of form I (supercoiled), whereas condensation and crosslinking of DNA accelerates the migration of form II (open circular)[51].Figure 7shows the electrophoretic patterns of plasmid DNA incubated with concentrations from 2,500 to 125 µM of the compounds. The compounds 3a, 3c, 2d and 4d showed slight impacts on DNA mobilities within 24 h, whereasthe compounds 2a, 3a, 4a, gem-1b, 4c, 1d, 3dand 5d exhibited alteration of the secondary structure.…”