title: 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.affiliation: Department of Cancer Biology, Metastasis Research Laboratory, The University of Texas MD Anderson Cancer Center, Houston, Texas (H.J.L., M.H., S.-J.K., H.Y., M.S.K., J.H., R.R.L., I.J.F.); Actelion Pharmaceuticals, Ltd., Allschwil, Switzerland (F.L., U.R.).
authors.forename: Ho Jeong
authors.initials: HJ
authors.lastname: Lee
authors.affiliation: Department of Cancer Biology, Metastasis Research Laboratory, The University of Texas MD Anderson Cancer Center, Houston, Texas (H.J.L., M.H., S.-J.K., H.Y., M.S.K., J.H., R.R.L., I.J.F.); Actelion Pharmaceuticals, Ltd., Allschwil, Switzerland (F.L., U.R.).
authors.forename: Masaki
authors.initials: M
authors.lastname: Hanibuchi
authors.affiliation: Department of Cancer Biology, Metastasis Research Laboratory, The University of Texas MD Anderson Cancer Center, Houston, Texas (H.J.L., M.H., S.-J.K., H.Y., M.S.K., J.H., R.R.L., I.J.F.); Actelion Pharmaceuticals, Ltd., Allschwil, Switzerland (F.L., U.R.).
authors.forename: Sun-Jin
authors.initials: SJ
authors.lastname: Kim
authors.affiliation: Department of Cancer Biology, Metastasis Research Laboratory, The University of Texas MD Anderson Cancer Center, Houston, Texas (H.J.L., M.H., S.-J.K., H.Y., M.S.K., J.H., R.R.L., I.J.F.); Actelion Pharmaceuticals, Ltd., Allschwil, Switzerland (F.L., U.R.).
authors.forename: Hyunkyung
authors.initials: H
authors.lastname: Yu
authors.affiliation: Department of Cancer Biology, Metastasis Research Laboratory, The University of Texas MD Anderson Cancer Center, Houston, Texas (H.J.L., M.H., S.-J.K., H.Y., M.S.K., J.H., R.R.L., I.J.F.); Actelion Pharmaceuticals, Ltd., Allschwil, Switzerland (F.L., U.R.).
authors.forename: Mark Seungwook
authors.initials: MS
authors.lastname: Kim
authors.affiliation: Department of Cancer Biology, Metastasis Research Laboratory, The University of Texas MD Anderson Cancer Center, Houston, Texas (H.J.L., M.H., S.-J.K., H.Y., M.S.K., J.H., R.R.L., I.J.F.); Actelion Pharmaceuticals, Ltd., Allschwil, Switzerland (F.L., U.R.).
authors.forename: Junqin
authors.initials: J
authors.lastname: He
authors.affiliation: Department of Cancer Biology, Metastasis Research Laboratory, The University of Texas MD Anderson Cancer Center, Houston, Texas (H.J.L., M.H., S.-J.K., H.Y., M.S.K., J.H., R.R.L., I.J.F.); Actelion Pharmaceuticals, Ltd., Allschwil, Switzerland (F.L., U.R.).
authors.forename: Robert R
authors.initials: RR
authors.lastname: Langley
authors.affiliation: Department of Cancer Biology, Metastasis Research Laboratory, The University of Texas MD Anderson Cancer Center, Houston, Texas (H.J.L., M.H., S.-J.K., H.Y., M.S.K., J.H., R.R.L., I.J.F.); Actelion Pharmaceuticals, Ltd., Allschwil, Switzerland (F.L., U.R.).
authors.forename: François
authors.initials: F
authors.lastname: Lehembre
authors.affiliation: Department of Cancer Biology, Metastasis Research Laboratory, The University of Texas MD Anderson Cancer Center, Houston, Texas (H.J.L., M.H., S.-J.K., H.Y., M.S.K., J.H., R.R.L., I.J.F.); Actelion Pharmaceuticals, Ltd., Allschwil, Switzerland (F.L., U.R.).
authors.forename: Urs
authors.initials: U
authors.lastname: Regenass
authors.affiliation: Department of Cancer Biology, Metastasis Research Laboratory, The University of Texas MD Anderson Cancer Center, Houston, Texas (H.J.L., M.H., S.-J.K., H.Y., M.S.K., J.H., R.R.L., I.J.F.); Actelion Pharmaceuticals, Ltd., Allschwil, Switzerland (F.L., U.R.).
authors.forename: Isaiah J
authors.initials: IJ
authors.lastname: Fidler
mesh_terms: D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D049109:Cell Proliferation / Q000187:drug effects; D004359:Drug Therapy, Combination; D005260:Female; D006801:Humans; D007124:Immunoenzyme Techniques; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000556:secondary; D051379:Mice; D008819:Mice, Nude; D041681:NIH 3T3 Cells; D017239:Paclitaxel / Q000494:pharmacology*; D011743:Pyrimidines / Q000494:pharmacology*; D017466:Receptors, Endothelin / Q000737:chemistry* / Q000378:metabolism; D013449:Sulfonamides / Q000494:pharmacology*; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D011743:Pyrimidines; D017466:Receptors, Endothelin; D013449:Sulfonamides; D017239:Paclitaxel; C533860:macitentan
keywords: astrocytes; brain metastases; endothelial cells; endothelin; macitentan