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Treatment of experimental human breast cancer and lung cancer brain metastases in mice by macitentan, a dual antagonist of endothelin receptors, combined with paclitaxel.

Abstract：

BACKGROUND:We recently demonstrated that brain endothelial cells and astrocytes protect cancer cells from chemotherapy through an endothelin-dependent signaling mechanism. Here, we evaluated the efficacy of macitentan, a dual endothelin receptor (ETAR and ETBR) antagonist, in the treatment of experimental breast and lung cancer brain metastases. METHODS:The effect of macitentan on astrocyte- and brain endothelial cell-mediated chemoprotective properties was measured in cytotoxic assays. We compared survival of mice bearing established MDA-MB-231 breast cancer or PC-14 non-small cell lung cancer (NSCLC) brain metastases that were treated with vehicle, macitentan, paclitaxel, or macitentan plus paclitaxel. Cell division, apoptosis, tumor vasculature, and expression of survival-related proteins were assessed by immunofluorescent microscopy. RESULTS:Cancer cells and tumor-associated endothelial cells expressed activated forms of AKT and MAPK in vehicle- and paclitaxel-treated groups in both metastasis models, but these proteins were downregulated in metastases of mice that received macitentan. The survival-related proteins Bcl2L1, Gsta5, and Twist1 that localized to cancer cells and tumor-associated endothelial cells in vehicle- and paclitaxel-treated tumors were suppressed by macitentan. Macitentan or paclitaxel alone had no effect on survival. However, when macitentan was combined with paclitaxel, we noted a significant reduction in cancer cell division and marked apoptosis of both cancer cells and tumor-associated endothelial cells. Moreover, macitentan plus paclitaxel therapy significantly increased overall survival by producing complete responses in 35 of 35 mice harboring brain metastases. CONCLUSIONS:Dual antagonism of ETAR and ETBR signaling sensitizes experimental brain metastases to paclitaxel and may represent a new therapeutic option for patients with brain metastases.

journal_name

Neuro Oncol

journal_title

Neuro-oncology

authors

Lee HJ,Hanibuchi M,Kim SJ,Yu H,Kim MS,He J,Langley RR,Lehembre F,Regenass U,Fidler IJ

doi

10.1093/neuonc/now037

subject

Has Abstract

pub_date

2016-04-01 00:00:00

pages

486-96

issue

eissn

1522-8517

issn

1523-5866

pii

now037

journal_volume

pub_type

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Treatment of experimental human breast cancer and lung cancer brain metastases in mice by macitentan, a dual antagonist of endothelin receptors, combined with paclitaxel.