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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.

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Antiproliferative effect for the MDA-MB-231 cell line upon exposure to Pd2Spm and DTX.Simple proliferation of MDA-MB-231 cells:–treated with either DTX (1-8x10-2 μM) or Pd2Spm (1–16 μM), in sole administration. 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, #p<0.0001 versus the control, for the same time-points).
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pone.0167218.g002: Antiproliferative effect for the MDA-MB-231 cell line upon exposure to Pd2Spm and DTX.Simple proliferation of MDA-MB-231 cells:–treated with either DTX (1-8x10-2 μM) or Pd2Spm (1–16 μM), in sole administration. 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, #p<0.0001 versus the control, for the same time-points).

Mentions: In order to achieve the proposed objectives, confirmation of the high anti-proliferative profile of DTX against the MDA-MB-231 cell line was the next step (Fig 2(A)). Although DTX was not very effective at the lowest concentration used (1.0x10-2 μM), for the two highest dosages (4x10-2 and 8x10-2 μM), it presented a dramatic effect (from 24 hours onwards of exposure). Comparison of the effects of DTX and Pd2Spm on the triple-negative breast cancer cells clearly evidenced that while the Pd-agent induced an increasing anti-proliferative activity at all the dosages tested (Fig 2(B)), for DTX a plateau is attained, the highest effect being measured at the 4x10-2 μM concentration and unaltered at 8x10-2 μM (Fig 2(A)).


Anti-Invasive and Anti-Proliferative Synergism between Docetaxel and a Polynuclear Pd-Spermine Agent
Antiproliferative effect for the MDA-MB-231 cell line upon exposure to Pd2Spm and DTX.Simple proliferation of MDA-MB-231 cells:–treated with either DTX (1-8x10-2 μM) or Pd2Spm (1–16 μM), in sole administration. 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, #p<0.0001 versus the control, for the same time-points).
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Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC5120851&req=5

pone.0167218.g002: Antiproliferative effect for the MDA-MB-231 cell line upon exposure to Pd2Spm and DTX.Simple proliferation of MDA-MB-231 cells:–treated with either DTX (1-8x10-2 μM) or Pd2Spm (1–16 μM), in sole administration. 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, #p<0.0001 versus the control, for the same time-points).
Mentions: In order to achieve the proposed objectives, confirmation of the high anti-proliferative profile of DTX against the MDA-MB-231 cell line was the next step (Fig 2(A)). Although DTX was not very effective at the lowest concentration used (1.0x10-2 μM), for the two highest dosages (4x10-2 and 8x10-2 μM), it presented a dramatic effect (from 24 hours onwards of exposure). Comparison of the effects of DTX and Pd2Spm on the triple-negative breast cancer cells clearly evidenced that while the Pd-agent induced an increasing anti-proliferative activity at all the dosages tested (Fig 2(B)), for DTX a plateau is attained, the highest effect being measured at the 4x10-2 μM concentration and unaltered at 8x10-2 μM (Fig 2(A)).

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