Lin Yueh-Te, Lin Joseph, Liu Yi-En, Hsu Kai-Wen, Hsieh Chang-Chi, Chen Dar-Ren, Wu Han-Tsang
Cancer Genome Research Center, Chang Gung Memorial Hospital at Linkou, Gueishan Dist., Taoyuan 333, Taiwan.
Comprehensive Breast Cancer Center, Changhua Christian Hospital, Changhua 500, Taiwan; Department of Animal Science and Biotechnology, Tunghai University, Taichung 407, Taiwan.
Transl Oncol. 2022 Jan;15(1):101302. doi: 10.1016/j.tranon.2021.101302. Epub 2021 Dec 7.
Breast cancer is common worldwide, and the estrogen receptor-positive subtype accounts for approximately 70% of breast cancer in women. Tamoxifen and fulvestrant are drugs currently used for endocrinal therapy. Breast cancer exhibiting endocrine resistance can undergo metastasis and lead to the death of breast cancer patients. Drug repurposing is an active area of research in clinical medicine. We found that nafamostat mesylate, clinically used for patients with pancreatitis and disseminated intravascular coagulation, acts as an anti-cancer drug for endocrine-resistant estrogen receptor-positive breast cancer (ERPBC). Epigenetic repression of CDK4 and CDK6 by nafamostat mesylate induced apoptosis and suppressed the metastasis of ERPBC through the deacetylation of Histone 3 Lysine 27. A combination of nafamostat mesylate and CDK4/6 inhibitor synergistically overcame endocrine resistance in ERPBC. Nafamostat mesylate might be an essential adjuvant or alternative drug for the treatment of endocrine-resistant ERPBC due to the low cost-efficiency of the CDK4/6 inhibitor.
乳腺癌在全球范围内都很常见，雌激素受体阳性亚型约占女性乳腺癌的70%。他莫昔芬和氟维司群是目前用于内分泌治疗的药物。表现出内分泌抵抗的乳腺癌会发生转移，并导致乳腺癌患者死亡。药物再利用是临床医学中一个活跃的研究领域。我们发现，临床上用于胰腺炎和弥散性血管内凝血患者的甲磺酸萘莫司他，可作为内分泌抵抗性雌激素受体阳性乳腺癌（ERPBC）的抗癌药物。甲磺酸萘莫司他对CDK4和CDK6的表观遗传抑制通过组蛋白3赖氨酸27的去乙酰化诱导细胞凋亡并抑制ERPBC的转移。甲磺酸萘莫司他与CDK4/6抑制剂联合使用可协同克服ERPBC中的内分泌抵抗。由于CDK4/6抑制剂的成本效益较低，甲磺酸萘莫司他可能是治疗内分泌抵抗性ERPBC的重要辅助药物或替代药物。
