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Anti-Invasive and Anti-Proliferative Synergism between Docetaxel and a Polynuclear Pd-Spermine Agent

View Article: PubMed Central - PubMed

ABSTRACT

The present work is aimed at evaluating the antitumour properties of a Pd(II) dinuclear complex with the biogenic polyamine spermine, by investigating: i) the anti-angiogenic and anti-migration properties of a Pd(II) dinuclear complex with spermine (Pd2Spm); ii) the anti-proliferative activity of Pd2Spm against a triple negative human breast carcinoma (MDA-MB-231); and finally iii) the putative interaction mediated by combination of Pd2Spm with Docetaxel. Anti-invasive (anti-angiogenic and anti-migratory) as well as anti-proliferative capacities were assessed, for different combination schemes and drug exposure times, using the CAM assay and VEGFR2 activity measurement, the MatrigelTM method and the SRB proliferation test. The results thus obtained evidence the ability of Pd2Spm to restrict angiogenesis and cell migration: Pd2Spm induced a marked inhibition of migration (43.8±12.2%), and a higher inhibition of angiogenesis (81.8±4.4% for total length values, at 4 μM) as compared to DTX at the clinical dosage 4x10-2 μM (26.4±14.4%; n = 4 to 11). Combination of Pd2Spm/DTX was more effective as anti-invasive and anti-proliferative than DTX or Pd2Spm in sole administration, which is compatible with the occurrence of synergism: for the anti-angiogenic effect, IC50(Pd2Spm/DTX) = 0.5/0.5x10-2 μM vs IC50(DTX) = 1.7x10-2 μM and IC50(Pd2Spm) = 1.6 μM. In conclusion, the reported effects of Pd2Spm on angiogenesis, migration and proliferation showed that this compound is a promising therapeutic agent against this type of breast cancer. Moreover, combined administration of Pd2Spm and DTX was found to trigger a substantial synergetic effect regarding angiogenesis inhibition as well as anti-migratory and anti-proliferative activities reinforcing the putative use of Pd(II) complexes in chemotherapeutic regimens. This is a significant outcome, aiming at the application of these combined strategies towards metastatic breast cancer (or other type of resistant cancers), justifying further studies that include pre-clinical trials.

No MeSH data available.


Related in: MedlinePlus

Anti-invasive assays in the presence of DTX, Pd2Spm and DTX with Pd2Spm combination.Quantitative CAM angiogenesis results in the presence of increasing concentrations of DTX, Pd2Spm and Pd2Spm/DTX. Eight days after fertilization, DTX, Pd2Spm, VEGF (positive control) or PBS (negative control) were added to the coverslip (previously sterilised and treated with hydrocortisone). After incubating the eggs for 48 hours, the CAMs were peeled off and photographed. Digital images were analysed using the Angiogenesis Analyser for Fiji [25]. (A)–number of extremities, nodes and branches; (B)–total branches length, total branching length, total length. Anti-migratory assays for the MDA-MB-231 cell line upon exposure to DTX, Pd2Spm and Pd2Spm/DTX combination, MDA-MB-231 cell invasion on MatrigelTM: (C)–Microscopic image (x10) of MDA-MB-231 cells treated with DTX (1x10-2 μM), Pd2Spm (4 μM) and Pd2Spm/DTX combination (1/1x10-2 μM) stained with crystal violet or (D) quantified by simple counting. The results are expressed as a percentage of the control ± SEM. The one-way ANOVA statistical analysis was used, and the Dunnett’s post-test was carried out to verify the significance of the obtained results (*p<0.05, **p<0.01, ***p<0.001 versus the control and #p<0.05 versus the VEGF).
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pone.0167218.g001: Anti-invasive assays in the presence of DTX, Pd2Spm and DTX with Pd2Spm combination.Quantitative CAM angiogenesis results in the presence of increasing concentrations of DTX, Pd2Spm and Pd2Spm/DTX. Eight days after fertilization, DTX, Pd2Spm, VEGF (positive control) or PBS (negative control) were added to the coverslip (previously sterilised and treated with hydrocortisone). After incubating the eggs for 48 hours, the CAMs were peeled off and photographed. Digital images were analysed using the Angiogenesis Analyser for Fiji [25]. (A)–number of extremities, nodes and branches; (B)–total branches length, total branching length, total length. Anti-migratory assays for the MDA-MB-231 cell line upon exposure to DTX, Pd2Spm and Pd2Spm/DTX combination, MDA-MB-231 cell invasion on MatrigelTM: (C)–Microscopic image (x10) of MDA-MB-231 cells treated with DTX (1x10-2 μM), Pd2Spm (4 μM) and Pd2Spm/DTX combination (1/1x10-2 μM) stained with crystal violet or (D) quantified by simple counting. The results are expressed as a percentage of the control ± SEM. The one-way ANOVA statistical analysis was used, and the Dunnett’s post-test was carried out to verify the significance of the obtained results (*p<0.05, **p<0.01, ***p<0.001 versus the control and #p<0.05 versus the VEGF).

Mentions: The impact of Pd2Spm in angiogenesis modulation was assessed by the CAM assay. Several parameters were counted and evaluated–number of extremities, branches and junctions, as well as total length, total branching length and total branches length. These were found to decrease in a concentration-dependent manner, in comparison to values obtained for both the control (PBS, where normal development of egg neovascularisation occurred) and VEGF conditions (where neovascularisation was stimulated). The effect elicited by increasing concentrations of Pd2Spm is depicted in Fig 1.


Anti-Invasive and Anti-Proliferative Synergism between Docetaxel and a Polynuclear Pd-Spermine Agent
Anti-invasive assays in the presence of DTX, Pd2Spm and DTX with Pd2Spm combination.Quantitative CAM angiogenesis results in the presence of increasing concentrations of DTX, Pd2Spm and Pd2Spm/DTX. Eight days after fertilization, DTX, Pd2Spm, VEGF (positive control) or PBS (negative control) were added to the coverslip (previously sterilised and treated with hydrocortisone). After incubating the eggs for 48 hours, the CAMs were peeled off and photographed. Digital images were analysed using the Angiogenesis Analyser for Fiji [25]. (A)–number of extremities, nodes and branches; (B)–total branches length, total branching length, total length. Anti-migratory assays for the MDA-MB-231 cell line upon exposure to DTX, Pd2Spm and Pd2Spm/DTX combination, MDA-MB-231 cell invasion on MatrigelTM: (C)–Microscopic image (x10) of MDA-MB-231 cells treated with DTX (1x10-2 μM), Pd2Spm (4 μM) and Pd2Spm/DTX combination (1/1x10-2 μM) stained with crystal violet or (D) quantified by simple counting. The results are expressed as a percentage of the control ± SEM. The one-way ANOVA statistical analysis was used, and the Dunnett’s post-test was carried out to verify the significance of the obtained results (*p<0.05, **p<0.01, ***p<0.001 versus the control and #p<0.05 versus the VEGF).
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Related In: Results  -  Collection

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pone.0167218.g001: Anti-invasive assays in the presence of DTX, Pd2Spm and DTX with Pd2Spm combination.Quantitative CAM angiogenesis results in the presence of increasing concentrations of DTX, Pd2Spm and Pd2Spm/DTX. Eight days after fertilization, DTX, Pd2Spm, VEGF (positive control) or PBS (negative control) were added to the coverslip (previously sterilised and treated with hydrocortisone). After incubating the eggs for 48 hours, the CAMs were peeled off and photographed. Digital images were analysed using the Angiogenesis Analyser for Fiji [25]. (A)–number of extremities, nodes and branches; (B)–total branches length, total branching length, total length. Anti-migratory assays for the MDA-MB-231 cell line upon exposure to DTX, Pd2Spm and Pd2Spm/DTX combination, MDA-MB-231 cell invasion on MatrigelTM: (C)–Microscopic image (x10) of MDA-MB-231 cells treated with DTX (1x10-2 μM), Pd2Spm (4 μM) and Pd2Spm/DTX combination (1/1x10-2 μM) stained with crystal violet or (D) quantified by simple counting. The results are expressed as a percentage of the control ± SEM. The one-way ANOVA statistical analysis was used, and the Dunnett’s post-test was carried out to verify the significance of the obtained results (*p<0.05, **p<0.01, ***p<0.001 versus the control and #p<0.05 versus the VEGF).
Mentions: The impact of Pd2Spm in angiogenesis modulation was assessed by the CAM assay. Several parameters were counted and evaluated–number of extremities, branches and junctions, as well as total length, total branching length and total branches length. These were found to decrease in a concentration-dependent manner, in comparison to values obtained for both the control (PBS, where normal development of egg neovascularisation occurred) and VEGF conditions (where neovascularisation was stimulated). The effect elicited by increasing concentrations of Pd2Spm is depicted in Fig 1.

View Article: PubMed Central - PubMed

ABSTRACT

The present work is aimed at evaluating the antitumour properties of a Pd(II) dinuclear complex with the biogenic polyamine spermine, by investigating: i) the anti-angiogenic and anti-migration properties of a Pd(II) dinuclear complex with spermine (Pd2Spm); ii) the anti-proliferative activity of Pd2Spm against a triple negative human breast carcinoma (MDA-MB-231); and finally iii) the putative interaction mediated by combination of Pd2Spm with Docetaxel. Anti-invasive (anti-angiogenic and anti-migratory) as well as anti-proliferative capacities were assessed, for different combination schemes and drug exposure times, using the CAM assay and VEGFR2 activity measurement, the MatrigelTM method and the SRB proliferation test. The results thus obtained evidence the ability of Pd2Spm to restrict angiogenesis and cell migration: Pd2Spm induced a marked inhibition of migration (43.8&plusmn;12.2%), and a higher inhibition of angiogenesis (81.8&plusmn;4.4% for total length values, at 4 &mu;M) as compared to DTX at the clinical dosage 4x10-2 &mu;M (26.4&plusmn;14.4%; n = 4 to 11). Combination of Pd2Spm/DTX was more effective as anti-invasive and anti-proliferative than DTX or Pd2Spm in sole administration, which is compatible with the occurrence of synergism: for the anti-angiogenic effect, IC50(Pd2Spm/DTX) = 0.5/0.5x10-2 &mu;M vs IC50(DTX) = 1.7x10-2 &mu;M and IC50(Pd2Spm) = 1.6 &mu;M. In conclusion, the reported effects of Pd2Spm on angiogenesis, migration and proliferation showed that this compound is a promising therapeutic agent against this type of breast cancer. Moreover, combined administration of Pd2Spm and DTX was found to trigger a substantial synergetic effect regarding angiogenesis inhibition as well as anti-migratory and anti-proliferative activities reinforcing the putative use of Pd(II) complexes in chemotherapeutic regimens. This is a significant outcome, aiming at the application of these combined strategies towards metastatic breast cancer (or other type of resistant cancers), justifying further studies that include pre-clinical trials.

No MeSH data available.


Related in: MedlinePlus