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.

• Authors: Ho Jeong Lee, Masaki Hanibuchi, Sun-Jin Kim, Hyunkyung Yu, Mark Seungwook Kim, Junqin He, Robert R Langley, François Lehembre, Urs Regenass, Isaiah J Fidler
• Journal: Neuro-oncology (Neuro Oncol) Vol. 18 Issue 4 Pg. 486-96 (Apr 2016) ISSN: 1523-5866 [Electronic] England
• PMID: 26995790 (Publication Type: Comparative Study, Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: © The Author(s) 2016. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For permissions, please e-mail: [email protected].

Chemical References

• Antineoplastic Agents, Phytogenic
• Pyrimidines
• Receptors, Endothelin
• Sulfonamides
• Paclitaxel
• macitentan

Topics

• Animals
• Antineoplastic Agents, Phytogenic (pharmacology)
• Apoptosis (drug effects)
• Breast Neoplasms (drug therapy, metabolism, pathology)
• Cell Proliferation (drug effects)
• Drug Therapy, Combination
• Female
• Humans
• Immunoenzyme Techniques
• Lung Neoplasms (drug therapy, metabolism, secondary)
• Mice
• Mice, Nude
• NIH 3T3 Cells
• Paclitaxel (pharmacology)
• Pyrimidines (pharmacology)
• Receptors, Endothelin (chemistry, metabolism)
• Sulfonamides (pharmacology)
• Tumor Cells, Cultured
• Xenograft Model Antitumor Assays