Cytotoxicity, cellular uptake, glutathione and DNA interactions of an antitumor large-ring Pt II chelate complex incorporating the cis-1,4-diaminocyclohexane carrier ligand.
Earlier studies have described promising antitumor activity of a large-ring chelate complex [PtCl(2)(cis-1,4-DACH)] (DACH=diaminocyclohexane). Encouraging antitumor activity of this analogue of cisplatin prompted us to perform studies focused on the mechanistic basis of pharmacological effects of this complex. Four early steps in the mechanism of biological activity of cisplatin have been delineated: cell entry, reactions with sulfur-containing compounds, platinum-DNA binding along with processing platinated DNA by proteins (enzymes) and DNA repair. Here, we describe comparative experiments (involving also cisplatin) revealing: (i) improved cytotoxicity (3.4-5.4-fold) of [PtCl(2)(cis-1,4-DACH)] in human tumor ovarian cell lines; (ii) enhanced cellular uptake (approximately 1.5-fold) of [PtCl(2)(cis-1,4-DACH)]; (iii) somewhat enhanced rate of reactions of [PtCl(2)(cis-1,4-DACH)] with glutathione (approximately 1.5-fold), but a similar rate of reactions with metallothionenin-2; (iv) enhanced rate of DNA binding of [PtCl(2)(cis-1,4-DACH)] in cell-free media (approximately 2-fold); (v) similar sequence preference of DNA binding of [PtCl(2)(cis-1,4-DACH)] in cell-free media; (vi) identical DNA interstrand cross-linking efficiency (6%); (vii) similar bending (32 degrees) and enhanced local unwinding (approximately 1.5-fold) induced in DNA by the major 1,2-GG-intrastrand cross-link; (viii) markedly enhanced inhibiting effects of DNA adducts of [PtCl(2)(cis-1,4-DACH)] on processivity of DNA polymerase; and (ix) a slightly lower efficiency of DNA repair systems to remove the adducts of [PtCl(2)(cis-1,4-DACH)] from DNA.
Institute of Biophysics, Academy of Sciences of the Czech Republic, v.v.i., Kralovopolska 135, CZ-61265 Brno, Czech Republic.
Jana
J
Kasparkova
Tereza
T
Suchankova
Anna
A
Halamikova
Lenka
L
Zerzankova
Oldrich
O
Vrana
Nicola
N
Margiotta
Giovanni
G
Natile
Viktor
V
Brabec
D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology; D002417:Cattle; D045744:Cell Line, Tumor; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism; D003514:Cyclohexylamines / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology; D004260:DNA Repair / Q000187:drug effects* / Q000502:physiology; D004273:DNA, Neoplasm / Q000378:metabolism*; D004337:Drug Carriers / Q000737:chemistry / Q000378:metabolism / Q000633:toxicity; D005978:Glutathione / Q000378:metabolism*; D006367:HeLa Cells; D006801:Humans; D008024:Ligands; D009944:Organoplatinum Compounds / Q000378:metabolism* / Q000633:toxicity*; D017671:Platinum Compounds / Q000737:chemistry / Q000378:metabolism / Q000633:toxicity; D011817:Rabbits
D000970:Antineoplastic Agents; D003514:Cyclohexylamines; D004273:DNA, Neoplasm; D004337:Drug Carriers; D008024:Ligands; D009944:Organoplatinum Compounds; D017671:Platinum Compounds; C030173:platinum chloride; C088969:1,4-diaminocyclohexane; D005978:Glutathione