title: Combinatorial therapy with tamoxifen and trifluoperazine effectively inhibits malignant peripheral nerve sheath tumor growth by targeting complementary signaling cascades.
abstract: Chemotherapeutic agents effective against malignant peripheral nerve sheath tumors (MPNSTs) are urgently needed. We recently found that tamoxifen potently impedes xenograft growth. In vitro, tamoxifen inhibits MPNST proliferation and survival in an estrogen receptor-independent manner; these effects are phenocopied by the calmodulin inhibitor trifluoperazine. The present study was performed to establish the mechanism of action of tamoxifen in vivo and optimize its therapeutic effectiveness. To determine if tamoxifen has estrogen receptor-dependent effects in vivo, we grafted MPNST cells in castrated and ovariectomized mice; xenograft growth was unaffected by reductions in sex hormones. To establish whether tamoxifen and trifluoperazine additively or synergistically impede MPNST growth, mice xenografted with neurofibromatosis type 1-associated or sporadic MPNST cells were treated with tamoxifen, trifluoperazine, or both drugs for 30 days. Both monotherapies inhibited graft growth by 50%, whereas combinatorial treatment maximally reduced graft mass by 90% and enhanced decreases in proliferation and survival. Kinomic analyses showed that tamoxifen and trifluoperazine have both shared and distinct targets in MPNSTs. In addition, trifluoperazine prevented tamoxifen-induced increases in serum/glucocorticoid regulated kinase 1, a protein linked to tamoxifen resistance. These findings suggest that combinatorial therapy with tamoxifen and trifluoperazine is effective against MPNSTs because these agents target complementary pathways that are essential for MPNST pathogenesis.
authors.affiliation: From the Departments of Pathology (SNB, ANT, SJB, KAR, SLC) and Medicine (JCK) and the Medical Scientist Training Program (SNB), University of Alabama at Birmingham, Birmingham, Alabama; and Department of Pathology and Laboratory Medicine (JFL, SLC), Medical University of South Carolina, Charleston, South Carolina.
authors.forename: Stephanie N
authors.initials: SN
authors.lastname: Brosius
authors.forename: Amy N
authors.initials: AN
authors.lastname: Turk
authors.forename: Stephanie J
authors.initials: SJ
authors.lastname: Byer
authors.forename: Jody Fromm
authors.initials: JF
authors.lastname: Longo
authors.forename: John C
authors.initials: JC
authors.lastname: Kappes
authors.forename: Kevin A
authors.initials: KA
authors.lastname: Roth
authors.forename: Steven L
authors.initials: SL
authors.lastname: Carroll
mesh_terms: D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage*; D049109:Cell Proliferation / Q000187:drug effects / Q000502:physiology; D016503:Drug Delivery Systems / Q000379:methods*; D005260:Female; D008297:Male; D051379:Mice; D009442:Neurilemmoma / Q000188:drug therapy* / Q000473:pathology; D015398:Signal Transduction / Q000187:drug effects* / Q000502:physiology; D013629:Tamoxifen / Q000008:administration & dosage; D016896:Treatment Outcome; D014268:Trifluoperazine / Q000008:administration & dosage; D023041:Xenograft Model Antitumor Assays / Q000379:methods
chemical_list: D013629:Tamoxifen; D014268:Trifluoperazine