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Eribulin mesylate exerts specific gene expression changes in pericytes and shortens pericyte-driven capillary network in vitro.

Agoulnik SI, Kawano S, Taylor N, Oestreicher J, Matsui J, Chow J, Oda Y, Funahashi Y - (2014)

Bottom Line: HUVECs and HBVPs were treated with either eribulin or paclitaxel and their antiproliferative effects were evaluated.To examine effects of the drugs on pericyte-driven in vitro angiogenesis, we compared lengths of capillary networks in co-cultures of HUVECs with HBVPs.In the functional endothelial-pericyte co-culture assay, eribulin, but not paclitaxel showed strong efficacy not only as a cytotoxic drug but also as a potent antivascular agent that affected pericyte-driven in vitro angiogenesis.

View Article: PubMed Central - HTML - PubMed

Affiliation: Eisai Inc, 4 Corporate Drive, Andover, MA 01810, USA. Yasuhiro_Funahashi@eisai.com.

ABSTRACT

Background: Eribulin mesylate is a synthetic macrocyclic ketone analog of the marine sponge natural product halichondrin B. Eribulin is a tubulin-binding drug and approved in many countries worldwide for treatment of certain patients with advanced breast cancer. Here we investigated antiproliferative and antiangiogenic effects of eribulin on vascular cells, human umbilical vein endothelial cells (HUVECs) and human brain vascular pericytes (HBVPs), in vitro in comparison with another tubulin-binding drug, paclitaxel.

Methods: HUVECs and HBVPs were treated with either eribulin or paclitaxel and their antiproliferative effects were evaluated. Global gene expression profiling changes caused by drug treatments were studied using Affymetrix microarray platform and custom TaqMan Low Density Cards. To examine effects of the drugs on pericyte-driven in vitro angiogenesis, we compared lengths of capillary networks in co-cultures of HUVECs with HBVPs.

Results: Both eribulin and paclitaxel showed potent activities in in vitro proliferation of HUVECs and HBVPs, with the half-maximal inhibitory concentrations (IC50) in low- to sub-nmol/L concentrations. When gene expression changes were assessed in HUVECs, the majority of affected genes overlapped for both treatments (59%), while in HBVPs, altered gene signatures were drug-dependent and the overlap was limited to just 12%. In HBVPs, eribulin selectively affected 11 pathways (p < 0.01) such as Cell Cycle Control of Chromosomal Replication. In contrast, paclitaxel was tended to regulate 27 pathways such as PI3K/AKT. Only 5 pathways were commonly affected by both treatments. In in vitro pericyte-driven angiogenesis model, paclitaxel showed limited activity while eribulin shortened the formed capillary networks of HUVECs driven by HBVPs at low nmol/L concentrations starting at day 3 after treatments.

Conclusions: Our findings suggest that pericytes, but not endothelial cells, responded differently, to two mechanistically-distinct tubulin-binding drugs, eribulin and paclitaxel. While eribulin and paclitaxel induced similar changes in gene expression in endothelial cells, in pericytes their altered gene expression was unique and drug-specific. In the functional endothelial-pericyte co-culture assay, eribulin, but not paclitaxel showed strong efficacy not only as a cytotoxic drug but also as a potent antivascular agent that affected pericyte-driven in vitro angiogenesis.

No MeSH data available.


Related in: MedlinePlus

Gene expression analysis of vascular cells treated with eribulin and paclitaxel. A. Number of differentially expressed genes in HUVECs treated with eribulin or paclitaxel. B. Comparison of eribulin and paclitaxel gene signatures in HUVECs by Venn diagram. C. Number of differentially expressed genes in HBVPs. D. Comparison of eribulin and paclitaxel gene signatures in HBVPs by Venn diagram. Analysis was restricted to genes with signal intensities >100, p-values < 0.05 and fold change levels of at least 1.5 in order to remove background effects.
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Figure 1: Gene expression analysis of vascular cells treated with eribulin and paclitaxel. A. Number of differentially expressed genes in HUVECs treated with eribulin or paclitaxel. B. Comparison of eribulin and paclitaxel gene signatures in HUVECs by Venn diagram. C. Number of differentially expressed genes in HBVPs. D. Comparison of eribulin and paclitaxel gene signatures in HBVPs by Venn diagram. Analysis was restricted to genes with signal intensities >100, p-values < 0.05 and fold change levels of at least 1.5 in order to remove background effects.

Mentions: In HUVECs, eribulin significantly altered expression of 321 genes compare to control vehicle-treated cells (Figure 1A). Paclitaxel caused transcriptional changes of 356 genes compare to control. When we compared these two signatures, more than 59% of genes overlapped between the two groups (Venn diagram, Figure 1B). It should be noted that all 251 overlapping genes changed expression in the same direction in eribulin and paclitaxel treated cells: 235 genes were down-regulated while 16 were up-regulated after both treatments. Interestingly, direct comparison of eribulin versus paclitaxel treatments showed significantly different expression changes in only 29 genes. Both treatments led to down-regulation, not up-regulation, of a majority of the affected genes in HUVECs (Additional file3).


Eribulin mesylate exerts specific gene expression changes in pericytes and shortens pericyte-driven capillary network in vitro.

Agoulnik SI, Kawano S, Taylor N, Oestreicher J, Matsui J, Chow J, Oda Y, Funahashi Y - (2014)

Gene expression analysis of vascular cells treated with eribulin and paclitaxel. A. Number of differentially expressed genes in HUVECs treated with eribulin or paclitaxel. B. Comparison of eribulin and paclitaxel gene signatures in HUVECs by Venn diagram. C. Number of differentially expressed genes in HBVPs. D. Comparison of eribulin and paclitaxel gene signatures in HBVPs by Venn diagram. Analysis was restricted to genes with signal intensities >100, p-values < 0.05 and fold change levels of at least 1.5 in order to remove background effects.
© Copyright Policy - open-access
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC4016419&req=5

Figure 1: Gene expression analysis of vascular cells treated with eribulin and paclitaxel. A. Number of differentially expressed genes in HUVECs treated with eribulin or paclitaxel. B. Comparison of eribulin and paclitaxel gene signatures in HUVECs by Venn diagram. C. Number of differentially expressed genes in HBVPs. D. Comparison of eribulin and paclitaxel gene signatures in HBVPs by Venn diagram. Analysis was restricted to genes with signal intensities >100, p-values < 0.05 and fold change levels of at least 1.5 in order to remove background effects.
Mentions: In HUVECs, eribulin significantly altered expression of 321 genes compare to control vehicle-treated cells (Figure 1A). Paclitaxel caused transcriptional changes of 356 genes compare to control. When we compared these two signatures, more than 59% of genes overlapped between the two groups (Venn diagram, Figure 1B). It should be noted that all 251 overlapping genes changed expression in the same direction in eribulin and paclitaxel treated cells: 235 genes were down-regulated while 16 were up-regulated after both treatments. Interestingly, direct comparison of eribulin versus paclitaxel treatments showed significantly different expression changes in only 29 genes. Both treatments led to down-regulation, not up-regulation, of a majority of the affected genes in HUVECs (Additional file3).

Bottom Line: HUVECs and HBVPs were treated with either eribulin or paclitaxel and their antiproliferative effects were evaluated.To examine effects of the drugs on pericyte-driven in vitro angiogenesis, we compared lengths of capillary networks in co-cultures of HUVECs with HBVPs.In the functional endothelial-pericyte co-culture assay, eribulin, but not paclitaxel showed strong efficacy not only as a cytotoxic drug but also as a potent antivascular agent that affected pericyte-driven in vitro angiogenesis.

View Article: PubMed Central - HTML - PubMed

Affiliation: Eisai Inc, 4 Corporate Drive, Andover, MA 01810, USA. Yasuhiro_Funahashi@eisai.com.

ABSTRACT

Background: Eribulin mesylate is a synthetic macrocyclic ketone analog of the marine sponge natural product halichondrin B. Eribulin is a tubulin-binding drug and approved in many countries worldwide for treatment of certain patients with advanced breast cancer. Here we investigated antiproliferative and antiangiogenic effects of eribulin on vascular cells, human umbilical vein endothelial cells (HUVECs) and human brain vascular pericytes (HBVPs), in vitro in comparison with another tubulin-binding drug, paclitaxel.

Methods: HUVECs and HBVPs were treated with either eribulin or paclitaxel and their antiproliferative effects were evaluated. Global gene expression profiling changes caused by drug treatments were studied using Affymetrix microarray platform and custom TaqMan Low Density Cards. To examine effects of the drugs on pericyte-driven in vitro angiogenesis, we compared lengths of capillary networks in co-cultures of HUVECs with HBVPs.

Results: Both eribulin and paclitaxel showed potent activities in in vitro proliferation of HUVECs and HBVPs, with the half-maximal inhibitory concentrations (IC50) in low- to sub-nmol/L concentrations. When gene expression changes were assessed in HUVECs, the majority of affected genes overlapped for both treatments (59%), while in HBVPs, altered gene signatures were drug-dependent and the overlap was limited to just 12%. In HBVPs, eribulin selectively affected 11 pathways (p < 0.01) such as Cell Cycle Control of Chromosomal Replication. In contrast, paclitaxel was tended to regulate 27 pathways such as PI3K/AKT. Only 5 pathways were commonly affected by both treatments. In in vitro pericyte-driven angiogenesis model, paclitaxel showed limited activity while eribulin shortened the formed capillary networks of HUVECs driven by HBVPs at low nmol/L concentrations starting at day 3 after treatments.

Conclusions: Our findings suggest that pericytes, but not endothelial cells, responded differently, to two mechanistically-distinct tubulin-binding drugs, eribulin and paclitaxel. While eribulin and paclitaxel induced similar changes in gene expression in endothelial cells, in pericytes their altered gene expression was unique and drug-specific. In the functional endothelial-pericyte co-culture assay, eribulin, but not paclitaxel showed strong efficacy not only as a cytotoxic drug but also as a potent antivascular agent that affected pericyte-driven in vitro angiogenesis.

No MeSH data available.


Related in: MedlinePlus