Cellular Pharmacology of Palladinum(III) Hematoporphyrin IX Complexes: Solution Stability, Antineoplastic and Apoptogenic Activity, DNA Binding, and Processing of DNA-Adducts.

Georgi Momekov,Daniela Tsekova,Galina Gencheva,Iva Ugrinova,Evdokia Pasheva

doi:10.3390/ijms19082451

Abstract

Two paramagnetic PdIII complexes of hematoporphyrin IX ((7,12-bis(1-hydroxyethyl)-3,8,13,17-tetramethyl-21H-23H-porphyn-2,18-dipropionic acid), Hp), namely a dinuclear one [PdIII2(Hp-3H)Cl3(H2O)5]·2PdCl2, Pd1 and a mononuclear metalloporphyrin type [PdIII(Hp-2H)Cl(H2O)]·H2O, Pd2 have been synthesized reproducibly and isolated as neutral compounds at different reaction conditions. Their structure and solution stability have been assayed by UV/Vis and EPR spectroscopy. The compounds researched have shown in vitro cell growth inhibitory effects at micromolar concentration against a panel of human tumor cell lines. A DNA fragmentation test in the HL-60 cell line has indicated that Pd1 causes comparable proapoptotic effects with regard to cisplatin but at substantially higher concentrations. Pd1 and cisplatin form intra-strand guanine bis-adducts as the palladium complex is less capable of forming DNA adducts. This demonstrates its cisplatin-dissimilar pharmacological profile. The test for efficient removal of DNA-adducts by the NER synthesis after modification of pBS plasmids with either cisplatin or Pd1 has manifested that the lesions induced by cisplatin are far better recognized and repaired compared those of Pd1. The study on the recognition and binding of the HMGB-1 protein to cisplatin or Pd1 modified DNA probes have shown that HMG proteins are less involved in the palladium agent cytotoxicity.

Highlights

Cisplatin and the clinically accepted platinum drugs have a great importance for the cancer treatment
The PdIII-complexes that undergo extensive biological screening have been obtained from the interaction of the initial palladium(II) salt ([PdIICl42−]) and hematoporphyrin IX
The complexes were synthesized during the interaction of an initial PdII compound as a chloride complex ([PdCl42−]) with the twofold deprotonated at peripheral propionic acid groups hematoporphyrin IX ligand ([Hp-2H]2−) in alkaline-aqueous medium achieved by adding KOH

Summary

Introduction

Cisplatin and the clinically accepted platinum drugs have a great importance for the cancer treatment. They have been applied in most anticancer chemotherapeutic regimens [1,2,3,4]. Cisplatin is still the most successful anticancer drug in the world, and is widely used in the treatment of a multitude of different cancers. Intensive research on drug development processes during the past years shows that the invention of universal compounds active against many cancer types is a task difficult to accomplish. The successful route leading to new efficient drugs inducing a better tumor response in individual patients is to design a pharmacological agent targeting specific abnormalities in particular cancer cells [4]

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