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 NF1-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. Additionally, 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.

The dopamine receptor antagonist trifluoperazine prevents phenotype conversion and improves survival in mouse models of glioblastoma

“…Mice bearing StrawRedexpressing GL261 tumors were treated with only saline or TFP starting on day 7. The TFP dose of 20 mg/kg, which has previously been reported as the MTD in mice (23), was well tolerated in our experiments. After an initial period of TFP-induced sedation that lasted 2 h to 3 h, the mice did not show any side effects, and TFP-treated animals did not show the tumorassociated weight loss that was observed in the control group (SI Appendix, Fig.…”

“…TFP was dissolved in sterile saline at a concentration of 2.5 mg/mL. All animals were treated with 20 mg/kg TFP, the published (maximum tolerated dose) MTD for mice (23).…”

Gene signature associated with benign neurofibroma transformation to malignant peripheral nerve sheath tumors

“…Due to MPNST are not sex steroid hormone sensitive, the ER modulator tamoxifen inhibits MPNST cultured cell growth independently of ER [ 30 , 60 ]. Combination therapies of tamoxifen and trifluoperazine have shown to be effective on treatment of sporadic and NF1-associated MPNST, suggesting the quick repurposing of these drugs for clinical and prophylactic uses.…”

Knockdown of HMGA2 regulates the level of autophagy via interactions between MSI2 and Beclin1 to inhibit NF1-associated malignant peripheral nerve sheath tumour growth

“…Female NSG mice (6 to 8 weeks old) were obtained from SPF Biotechnology Co. Ltd. (Beijing, China). Approximately 5 × 10 4 cells/5 μl (ST8814) were injected through a microsyringe into the sciatic nerve in mouse thighs to generate tumours for tissue transplantation according to the protocol by Brosius et al [26] After 4 weeks, the mice were intraperitoneally injected with D-luciferin (Caliper Life Sciences) and allowed to move freely for 10 min to promote substrate absorption. After being anaesthetized, the mice were subjected to whole-body live imaging using the IVIS Imaging System (Caliper Life Sciences).…”