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Biological evaluation of transdichloridoplatinum(II) complexes with 3- and 4-acetylpyridine in comparison to cisplatin.

Filipovic L, Arandelovic S, Gligorijevic N, Krivokuca A, Jankovic R, Srdic-Rajic T, Rakic G, Tesic Z, Radulovic S - Radiol Oncol (2013)

Bottom Line: Compound 2 displayed an apparent cytoselective profile, and flow cytometry analysis in HeLa cells indicated that 2 exerted antiproliferative effect through apoptosis induction, while 1 induced both apoptosis and necrosis.Action of 1 and 2, as analyzed by quantitative real-time PCR and Western blot, was associated with down-regulation of ERCC1.Both trans-complexes inhibited MMP-9 mRNA expression in HeLa, while 2 significantly abrogated in vitro tubulogenesis in MS1 cells.

View Article: PubMed Central - PubMed

Affiliation: Institute for Oncology and Radiology of Serbia, Belgrade, Serbia.

ABSTRACT

Background: In our previous study we reported the synthesis and cytotoxicity of two trans-platinum(II) complexes: trans-[PtCl2(3-acetylpyridine)2] (1) and trans-[PtCl2(4-acetylpyridine)2] (2), revealing significant cytotoxic potential of 2. In order to evaluate the mechanism underlying biological activity of both trans-Pt(II) isomers, comparative studies versus cisplatin were performed in HeLa, MRC-5 and MS1 cells.

Materials and methods: The cytotoxic activity of the investigated complexes was determined using SRB assay. The colagenolytic activity was determined using gelatin zymography, while the effect of platinum complexes on matrix metalloproteinases 2 and 9 mRNA expression was evaluated by quantitative real-time PCR. Apoptotic potential and cell cycle alterations were determined by FACS analyses. Western blot analysis was used to evaluate the effect on expression of DNA-repair enzyme ERCC1, and quantitative real-time PCR was used for the ERCC1 mRNA expression analysis. In vitro antiangiogenic potential was determined by tube formation assay. Platinum content in intracellular DNA and proteins was determined by inductively coupled plasma-optical emission spectrometry.

Results: Compound 2 displayed an apparent cytoselective profile, and flow cytometry analysis in HeLa cells indicated that 2 exerted antiproliferative effect through apoptosis induction, while 1 induced both apoptosis and necrosis. Action of 1 and 2, as analyzed by quantitative real-time PCR and Western blot, was associated with down-regulation of ERCC1. Both trans-complexes inhibited MMP-9 mRNA expression in HeLa, while 2 significantly abrogated in vitro tubulogenesis in MS1 cells.

Conclusions: The ability of 2 to induce multiple and selective in vitro cytotoxic effects encourages further investigations of trans-platinum(II) complexes with substituted pyridines.

No MeSH data available.


Related in: MedlinePlus

Structures of the investigated trans-platinum(II) complexes: trans-[PtCl2(3-acetylpyridine)2] 1; trans-[PtCl2(4-acetylpyridine)2] 2.
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f1-rado-47-04-346: Structures of the investigated trans-platinum(II) complexes: trans-[PtCl2(3-acetylpyridine)2] 1; trans-[PtCl2(4-acetylpyridine)2] 2.

Mentions: In our previous investigations, we have synthesized and characterized two trans-platinum(II) complexes, of structural formula trans-[PtCl2(L)2] with substituted pyridine ligands, L=n-acetylpyridine, (n = 3 or 4) (Figure 1). Cytotoxicity evaluation on the panel of tumor cell lines revealed potential of trans-[PtCl2(4-acetylpyridine)2] to exert activity in low micromolar range, with the highest cytotoxicity in HeLa cells, comparable to that of CDDP.23 Aim of this study was to investigate the molecular mechanisms underlying the in vitro biological activity of trans-[PtCl2(4-acetylpyridine)2] (complex 2) and its less cytotoxic structural isomer trans-[PtCl2(3-acetylpyridine)2] (complex 1), and to understand possible relations to their structural characteristics, such as the position of the acetyl substituent on the pyridine ring. Mechanistic studies were performed in comparison to CDDP in human cervix carcinoma cell line (HeLa), and two other cell lines: human normal lung fibroblast (MRC-5) cell line, which was used as a non-cancerous model system for in vitro toxicity evaluation, and murine endothelial cells immortalized by infection with a retrovirus encoding SV40 large T antigen (MS1), as a model system for in vitro testing of antiangiogenic effect.24 In order to test if the cytotoxic responses produced by compounds 1 and 2 in HeLa cells correlated with the platinum content in cellular DNA and to evaluate the mechanism of cytotoxic action, we studied the ability of complexes to bind intracellular DNA and proteins, and to induce DNA-damage related response, cell cycle alterations and apoptosis.


Biological evaluation of transdichloridoplatinum(II) complexes with 3- and 4-acetylpyridine in comparison to cisplatin.

Filipovic L, Arandelovic S, Gligorijevic N, Krivokuca A, Jankovic R, Srdic-Rajic T, Rakic G, Tesic Z, Radulovic S - Radiol Oncol (2013)

Structures of the investigated trans-platinum(II) complexes: trans-[PtCl2(3-acetylpyridine)2] 1; trans-[PtCl2(4-acetylpyridine)2] 2.
© Copyright Policy - open-access
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC3814279&req=5

f1-rado-47-04-346: Structures of the investigated trans-platinum(II) complexes: trans-[PtCl2(3-acetylpyridine)2] 1; trans-[PtCl2(4-acetylpyridine)2] 2.
Mentions: In our previous investigations, we have synthesized and characterized two trans-platinum(II) complexes, of structural formula trans-[PtCl2(L)2] with substituted pyridine ligands, L=n-acetylpyridine, (n = 3 or 4) (Figure 1). Cytotoxicity evaluation on the panel of tumor cell lines revealed potential of trans-[PtCl2(4-acetylpyridine)2] to exert activity in low micromolar range, with the highest cytotoxicity in HeLa cells, comparable to that of CDDP.23 Aim of this study was to investigate the molecular mechanisms underlying the in vitro biological activity of trans-[PtCl2(4-acetylpyridine)2] (complex 2) and its less cytotoxic structural isomer trans-[PtCl2(3-acetylpyridine)2] (complex 1), and to understand possible relations to their structural characteristics, such as the position of the acetyl substituent on the pyridine ring. Mechanistic studies were performed in comparison to CDDP in human cervix carcinoma cell line (HeLa), and two other cell lines: human normal lung fibroblast (MRC-5) cell line, which was used as a non-cancerous model system for in vitro toxicity evaluation, and murine endothelial cells immortalized by infection with a retrovirus encoding SV40 large T antigen (MS1), as a model system for in vitro testing of antiangiogenic effect.24 In order to test if the cytotoxic responses produced by compounds 1 and 2 in HeLa cells correlated with the platinum content in cellular DNA and to evaluate the mechanism of cytotoxic action, we studied the ability of complexes to bind intracellular DNA and proteins, and to induce DNA-damage related response, cell cycle alterations and apoptosis.

Bottom Line: Compound 2 displayed an apparent cytoselective profile, and flow cytometry analysis in HeLa cells indicated that 2 exerted antiproliferative effect through apoptosis induction, while 1 induced both apoptosis and necrosis.Action of 1 and 2, as analyzed by quantitative real-time PCR and Western blot, was associated with down-regulation of ERCC1.Both trans-complexes inhibited MMP-9 mRNA expression in HeLa, while 2 significantly abrogated in vitro tubulogenesis in MS1 cells.

View Article: PubMed Central - PubMed

Affiliation: Institute for Oncology and Radiology of Serbia, Belgrade, Serbia.

ABSTRACT

Background: In our previous study we reported the synthesis and cytotoxicity of two trans-platinum(II) complexes: trans-[PtCl2(3-acetylpyridine)2] (1) and trans-[PtCl2(4-acetylpyridine)2] (2), revealing significant cytotoxic potential of 2. In order to evaluate the mechanism underlying biological activity of both trans-Pt(II) isomers, comparative studies versus cisplatin were performed in HeLa, MRC-5 and MS1 cells.

Materials and methods: The cytotoxic activity of the investigated complexes was determined using SRB assay. The colagenolytic activity was determined using gelatin zymography, while the effect of platinum complexes on matrix metalloproteinases 2 and 9 mRNA expression was evaluated by quantitative real-time PCR. Apoptotic potential and cell cycle alterations were determined by FACS analyses. Western blot analysis was used to evaluate the effect on expression of DNA-repair enzyme ERCC1, and quantitative real-time PCR was used for the ERCC1 mRNA expression analysis. In vitro antiangiogenic potential was determined by tube formation assay. Platinum content in intracellular DNA and proteins was determined by inductively coupled plasma-optical emission spectrometry.

Results: Compound 2 displayed an apparent cytoselective profile, and flow cytometry analysis in HeLa cells indicated that 2 exerted antiproliferative effect through apoptosis induction, while 1 induced both apoptosis and necrosis. Action of 1 and 2, as analyzed by quantitative real-time PCR and Western blot, was associated with down-regulation of ERCC1. Both trans-complexes inhibited MMP-9 mRNA expression in HeLa, while 2 significantly abrogated in vitro tubulogenesis in MS1 cells.

Conclusions: The ability of 2 to induce multiple and selective in vitro cytotoxic effects encourages further investigations of trans-platinum(II) complexes with substituted pyridines.

No MeSH data available.


Related in: MedlinePlus