Combinatorial therapy with tamoxifen and trifluoperazine effectively inhibits malignant peripheral nerve sheath tumor growth by targeting complementary signaling cascades.
Combinatorial therapy with tamoxifen and trifluoperazine effectively inhibits malignant peripheral nerve sheath tumor growth by targeting complementary signaling cascades.
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DOI：
10.1097/nen.0000000000000126
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发表时间：
2014-11
影响因子：
3.2
通讯作者：
Carroll SL
中科院分区：
文献类型：
--
作者：
Brosius SN;Turk AN;Byer SJ;Longo JF;Kappes JC;Roth KA;Carroll SL
恶性周围神经鞘瘤（MPNSTs）的化疗药物是迫切需要的。我们最近发现，他莫昔芬有效地阻碍异种移植物的生长。在体外，他莫昔芬抑制MPNST的增殖和生存在雌激素受体的非依赖性方式，这些影响是由钙调蛋白抑制剂三氟拉嗪phenocopied。本研究旨在建立他莫昔芬在体内的作用机制，并优化其治疗效果。为了确定他莫昔芬是否具有体内雌激素受体依赖性作用，我们将MPNST细胞移植到去势和卵巢切除小鼠中;异种移植物生长不受性激素减少的影响。为了确定他莫昔芬和三氟拉嗪是否相加或协同阻碍MPNST生长，用他莫昔芬、三氟拉嗪或两种药物治疗异种移植有NF 1相关或散发性MPNST细胞的小鼠30天。这两种单一疗法抑制移植物生长的50%，而组合治疗最大限度地减少移植物质量的90%，并增强减少增殖和生存。基因组学分析表明，他莫昔芬和三氟拉嗪在MPNST中具有共同的和不同的靶点。此外，三氟拉嗪防止他莫昔芬诱导的血清/糖皮质激素调节激酶1（一种与他莫昔芬耐药性相关的蛋白质）升高。这些发现表明，他莫昔芬和三氟拉嗪的联合治疗对MPNST有效，因为这些药物靶向对MPNST发病机制至关重要的互补途径。
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.