Chen Jihui, Wang Zhipeng, Gao Shouhong, Wu Kejin, Bai Fang, Zhang Qiqiang, Wang Hongyu, Ye Qin, Xu Fengjing, Sun Hong, Lu Yunshu, Liu Yan
Department of Pharmacy, Xin Hua Hospital, Shanghai Jiao Tong University School of Medicine, 1665 Kongjiang Road, Shanghai, 200092, China.
Department of Pharmacy, Changzheng Hospital, Second Military Medical University, Shanghai, 200003, China.
Cancer Cell Int. 2021 Feb 25;21(1):136. doi: 10.1186/s12935-021-01842-x.
Pemetrexed, a new generation antifolate drug, has been approved for the treatment of locally advanced or metastatic breast cancer. However, factors affecting its efficacy and resistance have not been fully elucidated yet. ATP-binding cassette (ABC) transporters are predictors of prognosis as well as of adverse effects of several xenobiotics. This study was designed to explore whether ABC transporters affect pemetrexed resistance and can contribute to the optimization of breast cancer treatment regimen.
First, we measured the expression levels of ABC transporter family members in cell lines. Subsequently, we assessed the potential role of ABC transporters in conferring resistance to pemetrexed in primary breast cancer cells isolated from 34 breast cancer patients and the role of ABCC5 in mediating pemetrexed transport and apoptotic pathways in MCF-7 cells. Finally, the influence of ABCC5 expression on the therapeutic effect of pemetrexed was evaluated in an in vivo xenograft mouse model of breast cancer.
The expression levels of ABCC2, ABCC4, ABCC5, and ABCG2 significantly increased in the pan-resistant cell line, and the ABCC5 level in the MCF-7-ADR cell line was 5.21 times higher than that in the control group. ABCC5 expression was inversely correlated with pemetrexed sensitivity (IC, r = 0.741; p < 0.001) in breast cancer cells derived from 34 patients. Furthermore, we found that the expression level of ABCC5 influenced the efflux and cytotoxicity of pemetrexed in MCF-7 cells, with IC values of 0.06 and 0.20 μg/mL in ABCC5 knockout and over-expression cells, respectively. In the in vivo study, we observed that ABCC5 affected the sensitivity of pemetrexed in breast tumor-bearing mice, and the tumor volume was much larger in the ABCC5-overexpressing group than in the control group when compared with their own initial volumes (2.7-fold vs. 1.3-fold).
Our results indicated that ABCC5 expression was associated with pemetrexed resistance in vitro and in vivo, and it may serve as a target or biomarker for the optimization of pemetrexed regimen in breast cancer treatment.
培美曲塞是一种新一代抗叶酸药物，已被批准用于治疗局部晚期或转移性乳腺癌。然而，影响其疗效和耐药性的因素尚未完全阐明。ATP结合盒（ABC）转运蛋白是几种异生物素预后及不良反应的预测指标。本研究旨在探讨ABC转运蛋白是否影响培美曲塞耐药性，并有助于优化乳腺癌治疗方案。
首先，我们检测了细胞系中ABC转运蛋白家族成员的表达水平。随后，我们评估了ABC转运蛋白在34例乳腺癌患者分离的原发性乳腺癌细胞中赋予对培美曲塞耐药性的潜在作用，以及ABCC5在MCF-7细胞中介导培美曲塞转运和凋亡途径的作用。最后，在乳腺癌体内异种移植小鼠模型中评估ABCC5表达对培美曲塞治疗效果的影响。
泛耐药细胞系中ABCC2、ABCC4、ABCC5和ABCG2的表达水平显著升高，MCF-7-ADR细胞系中的ABCC5水平比对照组高5.21倍。在34例患者来源的乳腺癌细胞中，ABCC5表达与培美曲塞敏感性呈负相关（IC，r = 0.741；p < 0.001）。此外，我们发现ABCC5的表达水平影响MCF-7细胞中培美曲塞的外排和细胞毒性，ABCC5基因敲除和过表达细胞中的IC值分别为0.06和0.20μg/mL。在体内研究中，我们观察到ABCC5影响荷瘤小鼠对培美曲塞的敏感性，与对照组相比，ABCC5过表达组的肿瘤体积相对于其初始体积增大更为明显（2.7倍对1.3倍）。
我们的结果表明，ABCC5表达在体外和体内均与培美曲塞耐药性相关，它可能作为优化乳腺癌培美曲塞治疗方案的靶点或生物标志物。
