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

Abstract

BackgroundEribulin 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.MethodsHUVECs 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.ResultsBoth 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.ConclusionsOur 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.

Eribulin Mesylate: Mechanism of Action of a Unique Microtubule-Targeting Agent

“…Representative DCE-MRI images of the MX-1 tumors before and after eribulin treatment are shown in Figure 3, together with the average K trans measurements of the tumor rim and core (36). Similar results were obtained in a murine xenograft model, using Hoechst 33342 dye to measure perfusion (31). Tumors also showed an increase in the number of microvessels after eribulin treatment, consistent with increased perfusion.…”

“…The effects of eribulin on endothelial cells or pericytes alone or in co-culture were compared with the effects of paclitaxel (31). The proliferation of human umbilical endothelial cells was potently inhibited by both eribulin and paclitaxel, with similar IC 50 values of 0.54 nM and 0.41 nM, respectively.…”

MORAb-202, an Antibody–Drug Conjugate Utilizing Humanized Anti-human FRα Farletuzumab and the Microtubule-targeting Agent Eribulin, has Potent Antitumor Activity

“…In addition to its antimitotic effects, eribulin has also been demonstrated to have significant nonmitotic effects, which may contribute to its overall antitumor activity. Eribulin has been shown to inhibit cancer cell migration (15), increase tumor perfusion leading to increased tumor oxygenation and greater tumor penetration by subsequently administered agents (16)(17)(18), decrease circulating VEGF (18), and promote a mesenchymal-toepithelial transition in tumor phenotype (19,20). Eribulin has also been shown to cause less peripheral neuropathy compared with other MTAs in animal models and clinically (21)(22)(23).…”

Breast Cancer Patient with Li-Fraumeni Syndrome: A Case Report Highlighting the Importance of Multidisciplinary Management

“…We can speculate that chemosensitivity may increase in brain cancers as a result of damage to the blood-brain barrier by surgery and radiotherapy. We can also hypothesize that the excellent response of our patient may have been due to microvasculature remodeling and its anti-angiogenic effect, which is crucial in the development of GBM [37]. Finally, data in glioma cell lines indicate an association between the absence of functional TP53 and increased temozolomide sensitivity [38].…”