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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

A Diagram presenting cytotoxicity of the tested agents and cisplatin in terms of IC50 values, obtained for 48 h of drug action, by SRB assay. IC50 values present average (±SD) obtained from three or more independent experiments. Asterisks denotes p values, when comparing MRC-5 cells to HeLa cells, by ANOVA test: 1 (*) p > 0.05; 2 (**) p < 0.001; CDDP (*) p > 0.05; B Micrographs of HeLa cells or MRC-5 cells exposed to equimolar (5 mM) concentration of tested platinum complexes 1, 2 or CDDP, following 24 h treatment, versus control (non treated cells). Micrographs are one representative experiment selected of three and were obtained with Olympus digital camera connected to the inverted microscope (Carl Zeiss, Jena, Germany, objective 6.3/0.20).
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f2-rado-47-04-346: A Diagram presenting cytotoxicity of the tested agents and cisplatin in terms of IC50 values, obtained for 48 h of drug action, by SRB assay. IC50 values present average (±SD) obtained from three or more independent experiments. Asterisks denotes p values, when comparing MRC-5 cells to HeLa cells, by ANOVA test: 1 (*) p > 0.05; 2 (**) p < 0.001; CDDP (*) p > 0.05; B Micrographs of HeLa cells or MRC-5 cells exposed to equimolar (5 mM) concentration of tested platinum complexes 1, 2 or CDDP, following 24 h treatment, versus control (non treated cells). Micrographs are one representative experiment selected of three and were obtained with Olympus digital camera connected to the inverted microscope (Carl Zeiss, Jena, Germany, objective 6.3/0.20).

Mentions: In order to further investigate cytotoxic and cytoselective potential of the two trans-platinum isomers, in comparison to CDDP, growth inhibitory study was performed in MRC-5 cells, which were used as non-cancerous model for in vitro toxicity evaluation; and MS1 cells as in vitro model for testing of antiangiogenic effect. Cytotoxicity of the complexes summarized in terms of IC50 values, is presented in Figure 2A. IC50 values (mM) obtained for 48 h of continuous drug action in MRC-5 cells, may be arranged in increasing order as following: 15.4 ± 3.1 mM, for CDDP; 40.0 ± 11.1 mM for complex 1; and 56.4 ± 5.0 mM for 2, indicating lower toxicity of trans-complexes in non-cancerous cell model comparing to CDDP. Particularly, complex 2 exerted less cytotoxicity in MRC-5 cells than in HeLa, by a factor of approximately four-fold, indicating significant cytoselective potential toward neoplastic cells (p < 0.001). Both trans-complexes exhibited poor activity, in MS1 cells with IC50 values being: 76.3 ± 0.5 mM for complex 2; 34.5 ± 7.8 mM for complex 1; comparing to CDDP (IC50 18.6 ± 5.4 mM).


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)

A Diagram presenting cytotoxicity of the tested agents and cisplatin in terms of IC50 values, obtained for 48 h of drug action, by SRB assay. IC50 values present average (±SD) obtained from three or more independent experiments. Asterisks denotes p values, when comparing MRC-5 cells to HeLa cells, by ANOVA test: 1 (*) p > 0.05; 2 (**) p < 0.001; CDDP (*) p > 0.05; B Micrographs of HeLa cells or MRC-5 cells exposed to equimolar (5 mM) concentration of tested platinum complexes 1, 2 or CDDP, following 24 h treatment, versus control (non treated cells). Micrographs are one representative experiment selected of three and were obtained with Olympus digital camera connected to the inverted microscope (Carl Zeiss, Jena, Germany, objective 6.3/0.20).
© Copyright Policy - open-access
Related In: Results  -  Collection

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

f2-rado-47-04-346: A Diagram presenting cytotoxicity of the tested agents and cisplatin in terms of IC50 values, obtained for 48 h of drug action, by SRB assay. IC50 values present average (±SD) obtained from three or more independent experiments. Asterisks denotes p values, when comparing MRC-5 cells to HeLa cells, by ANOVA test: 1 (*) p > 0.05; 2 (**) p < 0.001; CDDP (*) p > 0.05; B Micrographs of HeLa cells or MRC-5 cells exposed to equimolar (5 mM) concentration of tested platinum complexes 1, 2 or CDDP, following 24 h treatment, versus control (non treated cells). Micrographs are one representative experiment selected of three and were obtained with Olympus digital camera connected to the inverted microscope (Carl Zeiss, Jena, Germany, objective 6.3/0.20).
Mentions: In order to further investigate cytotoxic and cytoselective potential of the two trans-platinum isomers, in comparison to CDDP, growth inhibitory study was performed in MRC-5 cells, which were used as non-cancerous model for in vitro toxicity evaluation; and MS1 cells as in vitro model for testing of antiangiogenic effect. Cytotoxicity of the complexes summarized in terms of IC50 values, is presented in Figure 2A. IC50 values (mM) obtained for 48 h of continuous drug action in MRC-5 cells, may be arranged in increasing order as following: 15.4 ± 3.1 mM, for CDDP; 40.0 ± 11.1 mM for complex 1; and 56.4 ± 5.0 mM for 2, indicating lower toxicity of trans-complexes in non-cancerous cell model comparing to CDDP. Particularly, complex 2 exerted less cytotoxicity in MRC-5 cells than in HeLa, by a factor of approximately four-fold, indicating significant cytoselective potential toward neoplastic cells (p < 0.001). Both trans-complexes exhibited poor activity, in MS1 cells with IC50 values being: 76.3 ± 0.5 mM for complex 2; 34.5 ± 7.8 mM for complex 1; comparing to CDDP (IC50 18.6 ± 5.4 mM).

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