In vitro pharmacological study of monomeric platinum(III) hematoporphyrin IX complexes.
Three stable mononuclear hematoporphyrin IX ((7,12-bis(1-hydroxyethyl)-3,8,13,17-tetramethyl-21H-23H-porphyn-2,18-dipropionic acid), Hp) complexes of Pt(III), namely cis-[ Pt(III)(NH(3))(2)(Hp(-3H))(H(2)O)(2)].H(2)O 1, [Pt(III)(Hp(-3H))(H(2)O)(2)].H(2)O 2 and [Pt(III)((O,O)Hp(-2H))Cl(H(2)O)(3)] 3 with distorted octahedral structure and (d(z)2)(1) ground state have been tested in vitro for antineoplastic activity in a panel of tumor cell lines. The novel platinum(III) complexes showed cytotoxic activity in a concentration-dependent manner with IC(50) values comparable to those of referent cytotoxic agent cisplatin together with lower cytotoxicity against renal cells. Further detailed evaluation of the active analogue 2 and the less active complex 3 showed that their potency greatly correlates with the ability to induce apoptosis and to bind DNA. Despite the structural dissimilarities between complex 2 and cisplatin, their DNA-adducts were equally effectively recognized and repaired by the nucleotide excision repair system. Complex 2 showed quite superior ability to accumulate in K-562 cells relative to cisplatin.
Momekov
Georgi
G
Department of Pharmacology, Pharmacotherapy and Toxicology, Faculty of Pharmacy, Medical University, Sofia, 2 Dunav Str, 1000 Sofia, Bulgaria. gmomekov@gmail.com
Karaivanova
Margarita
M
Ugrinova
Iva
I
Pasheva
Evdokia
E
Gencheva
Galina
G
Tsekova
Daniela
D
Arpadjan
Sonia
S
Bontchev
Panayot R
PR
D016923:Cell Death / Q000187:drug effects; D045744:Cell Line, Tumor; D053938:DNA Fragmentation / Q000187:drug effects; D004260:DNA Repair / Q000187:drug effects; D004273:DNA, Neoplasm / Q000378:metabolism; D004354:Drug Screening Assays, Antitumor; D004578:Electron Spin Resonance Spectroscopy; D057809:HEK293 Cells; D006415:Hematoporphyrins / Q000737:chemistry / Q000494:pharmacology* / Q000633:toxicity; D006801:Humans; D007668:Kidney / Q000187:drug effects / Q000473:pathology; D007700:Kinetics; D009944:Organoplatinum Compounds / Q000737:chemistry / Q000494:pharmacology* / Q000633:toxicity; D012996:Solutions; D013056:Spectrophotometry, Ultraviolet
D004273:DNA, Neoplasm; D006415:Hematoporphyrins; D009944:Organoplatinum Compounds; D012996:Solutions