Comparative studies of oxaliplatin-based platinum(iv) complexes in different in vitro and in vivo tumor models

Abstract

Using platinum(iv) prodrugs of clinically established platinum(ii) compounds is a strategy to overcome side effects and acquired resistances. We studied four oxaliplatin-derived platinum(iv) complexes with varying axial ligands in various in vitro and in vivo settings. The ability to interfere with DNA (pUC19) in the presence and absence of a reducing agent (ascorbic acid) was investigated in cell-free experiments. Cytotoxicity was compared under normoxic and hypoxic conditions in monolayer cultures and multicellular spheroids of colon carcinoma cell lines. Effects on the cell cycle were investigated by flow cytometry, and the capacity of inducing apoptosis was confirmed by flow cytometry and Western blotting. The anti-cancer activity of one complex was studied in vivo in immunodeficient and immunocompetent mice, and the platinum levels in various organs and the tumor after treatment were quantified. The results demonstrate that modification of the axial ligands can improve the cytotoxic potency. The complexes are able to interfere with plasmid DNA, which is enhanced by co-incubation with a reducing agent, and cause cell cycle perturbations. At higher concentrations, they induce apoptosis, but generate only low levels of reactive oxygen species. Two of the complexes increase the life span of leukemia (L1210) bearing mice, and one showed effects similar to oxaliplatin in a CT26 solid tumor model, despite the low platinum levels in the tumor. As in the case of oxaliplatin, activity in the latter model depends on an intact immune system. These findings show new perspectives for the development of platinum(iv) prodrugs of the anticancer agent oxaliplatin, combining bioreductive properties and immunogenic aspects.

The First Anticancer Tris(pyrazolyl)borate Molybdenum(IV) Complexes: Tested in Vitro and in Vivo—A Comparison of O,O‐, S,O‐, and N,N‐Chelate Effects

“…Since complexes 2 and 3 differ only in the position of the methyl group, it seemst hat ligand L3 (thioallomaltol) may favor interaction with DNA more than the ligand L2 (thiomaltol) does. In comparison with platinum complexes, which show av ery strong interaction with plasmid DNA, [51] the very low activity of complexes 2 and 3 in this experiment is indicative of atotallyd ifferent mode of action.…”

“…3‐Hydroxy‐2‐(4′‐chlorophenyl)chromen‐4‐thione ( L5 ) was synthesized by using the same procedure as for thiomaltol, described in the literature . The synthesis of potassium hydrotris[3‐isopropyl‐1 H‐ pyrazolyl]borate, KTp i Pr , was slightly modified from the one in the literature . NMR spectra were recorded with a Bruker FT‐NMR Avance III TM 500 MHz spectrometer at 500.10 ( 1 H), 125.75 ( 13 C), and 202.53 MHz ( 31 P), respectively.…”

“…[48] The synthesis of potassium hydrotris[3isopropyl-1H-pyrazolyl]borate, KTp iPr ,w as slightly modified from the one in the literature. [50,51] NMR spectra were recorded with a Bruker FT-NMR AvanceI II TM 500 MHz spectrometer at 500.10 ( 1 H), 125.75 ( 13 C), and 202.53 MHz ( 31 P), respectively.2 D-NMR measurements were recorded using standard pulse programs at 500.32 MHz ( 1 H) and 125.81 MHz ( 13 C). Elemental Analysis was carried out by the Microanalytical Laboratory of the University of Vienna on aP erkinElmer 2400 CHN elemental analyzer or aF ison-sEA 1108 CHNS-O Element Analyzer.X -ray diffraction analyses were performed on aB ruker X8 APEX II CCD diffractometer at 100 K. Electrospray ionization mass spectra were recorded on aB ruker AmaZon SL ion trap mass spectrometer (Bruker Daltonics GmbH).…”

Cancer cell growth inhibition by aroylhydrazone derivatives

“…The antiproliferative activity of the compounds was tested over different cancer cell lines and non-tumour cells. The effects were compared to the activity of Ox, a referent cytostatic, which is widely used in the clinic [47,48].…”

“…The effects of all tested hydrazones were compared to the activity of the referent cytostatic oxaliplatin (Ox), which is a drug widely used in the clinic [47,48].…”