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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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Combination effect of DTX and Pd2Spm on angiogenesis.Eight days after fertilization, Pd2Spm/DTX, VEGF (positive control) or PBS (negative control) was 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)–representative digital CAM image; (B)–quantitative CAM angiogenesis in the presence of increasing concentrations of Pd2Spm/DTX; (C) Inhibition of VEGFR2 activity in the presence of IC50 concentrations of Pd2Spm/DTX (determined by the CAM assay) and SU5416 –semaxanib (VEGFR2 inhibitor). 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 versus the control).
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pone.0167218.g003: Combination effect of DTX and Pd2Spm on angiogenesis.Eight days after fertilization, Pd2Spm/DTX, VEGF (positive control) or PBS (negative control) was 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)–representative digital CAM image; (B)–quantitative CAM angiogenesis in the presence of increasing concentrations of Pd2Spm/DTX; (C) Inhibition of VEGFR2 activity in the presence of IC50 concentrations of Pd2Spm/DTX (determined by the CAM assay) and SU5416 –semaxanib (VEGFR2 inhibitor). 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 versus the control).

Mentions: Combination therapy schemes intended to enhance cytostatic activity while decreasing the dosage of each individual component, thus leading to reduced acquired resistance and toxicity, are of the utmost importance mainly when synergism is achieved. DTX is an established anti-mitotic taxane-type drug used against several types of cancer (namely TNBC [12], hormone-refractory prostate and lung cancers), but it is generally administered in combination regimes to avoid chemoresistance [34] Pd2Spm/DTX combinations were assessed, in search for an additive or synergistic interaction between both drugs (Figs 1 and 3). Their association prompted an increase of the anti-angiogenic effect when compared to the effect observed for each individual compound: 77.7±11.2% for total branching length values versus 42.5±14.9% and 49.5±11.5% for DTX and Pd2Spm alone, respectively. At lower concentrations of the combined Pd2Spm– 1 μM/DTX– 1x10-2 μM, a statistically significant reduction in blood vessels development was observed when compared to the results observed in control conditions: above 50% in the number of extremities (51.6±12.3%), nodes (60.1±9.5%) and branches (58.0±12.6%). Similar results were obtained with total branching length (64.6±11.2%), total branches length (67.0±9.8%) and total length (58.7±9.7%) (n = 4 to 11).


Anti-Invasive and Anti-Proliferative Synergism between Docetaxel and a Polynuclear Pd-Spermine Agent
Combination effect of DTX and Pd2Spm on angiogenesis.Eight days after fertilization, Pd2Spm/DTX, VEGF (positive control) or PBS (negative control) was 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)–representative digital CAM image; (B)–quantitative CAM angiogenesis in the presence of increasing concentrations of Pd2Spm/DTX; (C) Inhibition of VEGFR2 activity in the presence of IC50 concentrations of Pd2Spm/DTX (determined by the CAM assay) and SU5416 –semaxanib (VEGFR2 inhibitor). 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 versus the control).
© Copyright Policy
Related In: Results  -  Collection

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getmorefigures.php?uid=PMC5120851&req=5

pone.0167218.g003: Combination effect of DTX and Pd2Spm on angiogenesis.Eight days after fertilization, Pd2Spm/DTX, VEGF (positive control) or PBS (negative control) was 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)–representative digital CAM image; (B)–quantitative CAM angiogenesis in the presence of increasing concentrations of Pd2Spm/DTX; (C) Inhibition of VEGFR2 activity in the presence of IC50 concentrations of Pd2Spm/DTX (determined by the CAM assay) and SU5416 –semaxanib (VEGFR2 inhibitor). 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 versus the control).
Mentions: Combination therapy schemes intended to enhance cytostatic activity while decreasing the dosage of each individual component, thus leading to reduced acquired resistance and toxicity, are of the utmost importance mainly when synergism is achieved. DTX is an established anti-mitotic taxane-type drug used against several types of cancer (namely TNBC [12], hormone-refractory prostate and lung cancers), but it is generally administered in combination regimes to avoid chemoresistance [34] Pd2Spm/DTX combinations were assessed, in search for an additive or synergistic interaction between both drugs (Figs 1 and 3). Their association prompted an increase of the anti-angiogenic effect when compared to the effect observed for each individual compound: 77.7±11.2% for total branching length values versus 42.5±14.9% and 49.5±11.5% for DTX and Pd2Spm alone, respectively. At lower concentrations of the combined Pd2Spm– 1 μM/DTX– 1x10-2 μM, a statistically significant reduction in blood vessels development was observed when compared to the results observed in control conditions: above 50% in the number of extremities (51.6±12.3%), nodes (60.1±9.5%) and branches (58.0±12.6%). Similar results were obtained with total branching length (64.6±11.2%), total branches length (67.0±9.8%) and total length (58.7±9.7%) (n = 4 to 11).

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