Qiao En-Qi, Yang Hong-Jian, Yu Xing-Fei, Gong Li-Jie, Zhang Xi-Ping, Chen Dao-Bao
Department of Breast Tumor Surgery, Cancer Hospital of University of Chinese Academy of Sciences, Zhejiang Cancer Hospital, Hangzhou, China.
Ann Transl Med. 2021 Sep;9(17):1389. doi: 10.21037/atm-21-4199.
Triple-negative breast cancer (TNBC) is characterized by its aggressiveness and poor prognosis. Docetaxel is the common chemotherapeutic drug used in the treatment of TNBC. However, resistance to docetaxel has limited the effectiveness of TNBC treatment. Petroleum ether extracts of (PECZ) can inhibit the proliferation of MDA-MB-231 cells. However, the effect of PECZ on docetaxel resistance is not clear.
A docetaxel-resistant MDA-MB-231 (MDA-MB-231/docetaxel) cell line was established, and Cell Counting Kit-8 (CCK-8), quantitative real-time PCR (qRT-PCR), and western blotting assays were used to evaluate the effect of docetaxel resistance in MDA-MB-231 cells. Next, CCK-8 was also performed to detect the effect of docetaxel or the combination treatment of docetaxel and PECZ on the proliferation of MDA-MB-231/docetaxel cells. Thereafter, MDA-MB-231/docetaxel cells were subcutaneously injected into nude mice to induce a TNBC xenograft model, and the mice were divided into a model group, docetaxel group, PECZ group, and combination of docetaxel and PECZ group. Subsequently, hematoxylin and eosin (HE) staining, immunohistochemical, qRT-PCR, and western blotting were used to estimate the effect of pre-treatment with PECZ on docetaxel tolerance reversal.
PECZ significantly inhibited the expression of pregnane X receptor (PXR), multidrug resistance 1 (MDR1), breast cancer resistance protein (BCRP), and cytochrome P-450 (CYP3A4) in MDA-MB-231/docetaxel cells. Only higher concentrations of docetaxel could inhibit the viability of MDA-MB-231/docetaxel cells. When pre-treated with PECZ, lower concentrations of docetaxel could significantly inhibit cell viability. Meanwhile, combination treatment also reduced the tumor volume, ameliorated the pathological change of tumor tissues, and down-regulated the expressions of PXR, MDR1, BCRP, and CYP3A4 (according to HE staining, immunohistochemical, qRT-PCR and western blotting results ).
Our research showed that PECZ reversed docetaxel resistance in TNBC by PXR both and , which provides the basis for further investigations into the potential therapeutic impact of docetaxel resistance in TNBC.
三阴性乳腺癌（TNBC）具有侵袭性强和预后差的特点。多西他赛是用于治疗TNBC的常用化疗药物。然而，对多西他赛的耐药性限制了TNBC治疗的有效性。[植物名称]的石油醚提取物（PECZ）可抑制MDA-MB-231细胞的增殖。然而，PECZ对多西他赛耐药性的影响尚不清楚。
建立多西他赛耐药的MDA-MB-231（MDA-MB-231/多西他赛）细胞系，采用细胞计数试剂盒-8（CCK-8）、定量实时聚合酶链反应（qRT-PCR）和蛋白质免疫印迹法评估MDA-MB-231细胞中多西他赛耐药性的影响。接下来，还进行CCK-8检测多西他赛或多西他赛与PECZ联合治疗对MDA-MB-231/多西他赛细胞增殖的影响。此后，将MDA-MB-231/多西他赛细胞皮下注射到裸鼠体内以诱导TNBC异种移植模型，将小鼠分为模型组、多西他赛组、PECZ组和多西他赛与PECZ联合组。随后，采用苏木精-伊红（HE）染色、免疫组织化学、qRT-PCR和蛋白质免疫印迹法评估PECZ预处理对多西他赛耐受性逆转的影响。
PECZ显著抑制MDA-MB-231/多西他赛细胞中孕烷X受体（PXR）、多药耐药蛋白1（MDR1）、乳腺癌耐药蛋白（BCRP）和细胞色素P-450（CYP3A4）的表达。只有较高浓度的多西他赛才能抑制MDA-MB-231/多西他赛细胞的活力。当用PECZ预处理时，较低浓度的多西他赛就能显著抑制细胞活力。同时，联合治疗还减小了肿瘤体积，改善了肿瘤组织的病理变化，并下调了PXR、MDR1、BCRP和CYP3A4的表达（根据HE染色、免疫组织化学、qRT-PCR和蛋白质免疫印迹结果）。
我们的研究表明，PECZ通过PXR在体内和体外逆转了TNBC对多西他赛的耐药性，这为进一步研究TNBC中多西他赛耐药性的潜在治疗影响提供了依据。
