Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA.
Department of Neurosurgery, Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA.
Genes (Basel). 2020 Jul 8;11(7):762. doi: 10.3390/genes11070762.
Patients with RASopathy Neurofibromatosis 1 (NF1) are at a markedly increased risk of the development of benign and malignant tumors. Malignant tumors are often recalcitrant to treatments and associated with poor survival; however, no chemopreventative strategies currently exist. We thus evaluated the effect of mebendazole, alone or in combination with cyclooxygenase-2 (COX-2) inhibitors, on the prevention of NF1-related malignancies in a (NPcis) mouse model of NF1. Our in vitro findings showed that mebendazole (MBZ) inhibits the growth of NF1-related malignant peripheral nerve sheath tumors (MPNSTs) through a reduction in activated guanosine triphosphate (GTP)-bound Ras. The daily MBZ treatment of NPcis mice dosed at 195 mg/kg daily, initiated 60 days after birth, substantially delayed the formation of solid malignancies and increased median survival ( < 0.0001). Compared to placebo-treated mice, phosphorylated extracellular signal-regulated kinase (pERK) levels were decreased in the malignancies of MBZ-treated mice. The combination of MBZ with COX-2 inhibitor celecoxib (CXB) further enhanced the chemopreventative effect in female mice beyond each drug alone. These findings demonstrate the feasibility of a prevention strategy for malignancy development in high-risk NF1 individuals.
患有 RASopathy 神经纤维瘤病 1 型 (NF1) 的患者发生良性和恶性肿瘤的风险显著增加。恶性肿瘤通常对治疗有抗药性，且生存预后较差；然而，目前尚无化学预防策略。因此，我们评估了单独使用苯并咪唑（MBZ）或与环氧化酶-2 (COX-2) 抑制剂联合使用对 NF1 相关恶性肿瘤的预防作用，在 NF1 的 NPcis 小鼠模型中进行了研究。我们的体外研究结果表明，MBZ 通过减少激活的鸟苷三磷酸 (GTP)-结合 Ras 来抑制 NF1 相关的恶性周围神经鞘瘤 (MPNST) 的生长。在出生后 60 天开始，以 195mg/kg/天的剂量每天给 NPcis 小鼠施用 MBZ 治疗，可显著延迟实体恶性肿瘤的形成并延长中位生存期 ( < 0.0001)。与安慰剂治疗的小鼠相比，MBZ 治疗的小鼠的恶性肿瘤中磷酸化细胞外信号调节激酶 (pERK) 水平降低。与单独使用每种药物相比，MBZ 与 COX-2 抑制剂塞来昔布 (CXB) 的联合使用进一步增强了雌性小鼠的化学预防效果。这些发现表明针对高危 NF1 个体恶性肿瘤发展的预防策略是可行的。
