Gründker Carsten, Wokoun Ulrike, Hellriegel Martin, Emons Günter
Department of Gynecology and Obstetrics, Georg-August-University, Göttingen, Germany.
J Obstet Gynaecol Res. 2019 Jul;45(7):1334-1342. doi: 10.1111/jog.13980. Epub 2019 Apr 23.
A characteristic of cancer cells including triple-negative breast cancers (TNBC) is an increased aerobic glycolysis for ATP production representing a selective therapeutic target. More than 70% of TNBC express gonadotropin-releasing hormone receptors (GnRH-R). These receptors can be used for targeted chemotherapy with cytotoxic GnRH agonists such as Zoptarelin Doxorubicin, in which doxorubicin is covalently linked to [D-Lys ]GnRH. In this study, we have analyzed whether inhibition of aerobic glycolysis can enhance the antitumor efficacy of GnRH-R-targeted chemotherapy using Zoptarelin Doxorubicin.
Triple-negative breast cancers cell lines MDA-MB-231 and HCC1806 were treated with Zoptarelin Doxorubicin, glycolysis inhibitor 2-deoxy-D-glucose (2DG) or the combination of both agents. Cell viability was measured using Alamar blue. Induction of apoptosis was quantified by measurement of loss of mitochondrial membrane potential. In vivo experiments were performed using nude mice bearing xenografted MDA-MB-231 tumors.
Treatment of TNBC cells with Zoptarelin Doxorubicin or with 2DG resulted in a significant decrease of cell viability and a significant increase of apoptosis. Treatment with Zoptarelin Doxorubicin in combination with 2DG resulted in significantly reduced viability and enhanced apoptosis compared with single-agent treatments. Combinational index (CI) analysis revealed the co-treatment effect as a synergistic. The antitumor effects of Zoptarelin Doxorubicin or 2DG were confirmed in nude mice. The tumor reducing effects of Zoptarelin Doxorubicin were enhanced by combination with 2DG.
The glycolytic phenotype of TNBC can be used to improve antitumor therapies. Co-treatment of Zoptarelin Doxorubicin with glycolysis inhibitor 2DG might be a suitable therapeutic option for GnRH receptor-positive TNBC.
癌细胞（包括三阴性乳腺癌（TNBC））的一个特征是有氧糖酵解增加以产生三磷酸腺苷（ATP），这是一个选择性治疗靶点。超过70%的三阴性乳腺癌表达促性腺激素释放激素受体（GnRH-R）。这些受体可用于用细胞毒性GnRH激动剂（如左炔诺孕酮阿霉素，其中阿霉素与[D-赖氨酸]GnRH共价连接）进行靶向化疗。在本研究中，我们分析了抑制有氧糖酵解是否能增强使用左炔诺孕酮阿霉素进行的GnRH-R靶向化疗的抗肿瘤疗效。
用左炔诺孕酮阿霉素、糖酵解抑制剂2-脱氧-D-葡萄糖（2DG）或两种药物的组合处理三阴性乳腺癌细胞系MDA-MB-231和HCC1806。使用阿拉玛蓝测定细胞活力。通过测量线粒体膜电位的丧失来定量凋亡诱导。使用携带异种移植MDA-MB-231肿瘤的裸鼠进行体内实验。
用左炔诺孕酮阿霉素或2DG处理三阴性乳腺癌细胞导致细胞活力显著降低和凋亡显著增加。与单药治疗相比，左炔诺孕酮阿霉素与2DG联合治疗导致活力显著降低和凋亡增强。联合指数（CI）分析显示联合治疗效果为协同作用。左炔诺孕酮阿霉素或2DG的抗肿瘤作用在裸鼠中得到证实。左炔诺孕酮阿霉素与2DG联合使用增强了肿瘤缩小作用。
三阴性乳腺癌的糖酵解表型可用于改善抗肿瘤治疗。左炔诺孕酮阿霉素与糖酵解抑制剂2DG联合治疗可能是GnRH受体阳性三阴性乳腺癌的合适治疗选择。
