ER阳性乳腺癌中西达本胺逆转内分泌耐药-《深圳大学学报理工版》

文章信息/Info

Title:: Chidamide reverses endocrine resistance in estrogen receptor-positive breast cancer

Author(s):: ZHOU You; WANG Yanan; ZHANG Kun; ZHU Jingzhong; and NING Zhiqiang; Shenzhen Chipscreen Biosciences Ltd., Shenzhen 518057, Guangdong Province, P.R.China

Keywords:: pharmacology; breast cancer; chidamide; endocrine therapy; tamoxifen; fulvestrant; epidermal growth factor

摘要:: 内分泌治疗是雌激素受体阳性乳腺癌的主要治疗手段，但耐药的发生限制了其应用，本研究试验证组蛋白去乙酰化酶抑制剂西达本胺是否可用于逆转雌激素受体阳性乳腺癌内分泌耐药．通过MTS细胞增殖检测实验发现，4-羟他莫西芬与西达本胺单药均对雌激素受体阳性乳腺癌细胞MCF-7的增殖具有一定抑制作用，且在两药联合时表现为药效叠加．表皮生长因子可诱导MCF-7对4-羟他莫西芬的耐药，而西达本胺可逆转这种耐药．通过Western Blot实验发现西达本胺可抑制表皮生长因子引起的MEK、ERK、AKT等激酶的磷酸化，并可抑制雌激素受体的磷酸化．原位移植瘤动物模型的体内药效实验也显示药物联用组比单药组更强的抑瘤作用．上述研究结果表明西达本胺在雌激素受体阳性乳腺癌细胞中具有逆转内分泌耐药的作用，作用机制可能与其对表皮生长因子下游通路及雌激素受体活化通路的抑制有关．

Abstract:: Endocrine therapy is the mainstay of treatment for estrogen receptor-positive breast cancer, but the occurrence of drug resistance limits its application. The aim of this study is to explore if chidamide, a histone deacetylase inhibitor, can be used for reversing endocrine resistance in estrogen receptor-positive breast cancer. MTS cell proliferation assay shows that monotherapy with 4-hydroxytamoxifen and chidamide have certain inhibitory effects on the proliferation of MCF-7 (estrogen receptor-positive breast cancer cell line), and additive effects upon combination. Epidermal growth factor induces resistance of MCF-7 to 4- hydroxytamoxifen, while chidamide can reverse this resistance. Western blot experiment shows that epidermal growth factor-induced phosphorylation of MEK, ERK, AKT can be reduced by chidamide, as well as the phosphorylation of estrogen receptor. In vivo efficacy in orthotopic transplantation breast tumor models also indicate that the effect of combination of chidamide and fulvestrant is more visible compared with monotherapy. These findings suggest that chidamide can reverse epidermal growth factor induced endocrine resistance in estrogen receptor positive breast cancer cells, and this reverse effect may be related with its inhibition of the pathways downstream of the epidermal growth factor and the pathway of activation of estrogen receptor.