期刊
GENES
卷 11, 期 7, 页码 -出版社
MDPI
DOI: 10.3390/genes11070762
关键词
neurofibromatosis 1 (NF1); mebendazole (MBZ); COX-2 inhibitor; MPNST; malignancy; sarcoma; chemoprevention
资金
- Children's Tumor Foundation Drug Discovery Initiative (DDI) Award
- Department of Defense (DOD) [W81XWH1810236]
- NCI [5K08CA230179]
- U.S. Department of Defense (DOD) [W81XWH1810236] Funding Source: U.S. Department of Defense (DOD)
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 acisNf1+/-;Tp53+/-(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 (p< 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.
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