Department of Gynecology and Obstetrics, Georg-August-University, Göttingen, Germany.
Oncol Rep. 2011 May;25(5):1481-7. doi: 10.3892/or.2011.1188. Epub 2011 Feb 17.
Triple-negative breast cancer does not express estrogen and progesterone receptors and there is no overexpression/amplification of the HER2-neu gene. Therefore, this subtype of breast cancer lacks the benefits of specific therapies which target these receptors. About 60% of all human breast cancers express receptors for luteinizing hormone releasing hormone (LHRH, GnRH), which might be used as a target. The LHRH receptor can be used for targeted chemotherapy with cytotoxic luteinizing hormone releasing hormone agonists such as AEZS-108 (AN-152), in which doxorubicin is linked to [D-Lys6]LHRH. In the present study we have analyzed by in vitro and in vivo experiments whether the cytotoxic LHRH agonist AEZS-108 (AN-152) induces apoptosis in triple-negative human breast cancer cells that express LHRH receptors. LHRH receptor expression in tumor biopsy specimens of triple-negative breast cancers was tested using immunohistochemistry. Cell proliferation was analyzed using alamar blue proliferation assay. Induction of apoptosis was quantified by measurement of loss of mitochondrial membrane potential. In vivo experiments were performed using nude mice bearing xenografted human breast tumors.Thirty-one of 42 triple-negative breast cancers (73.8%) expressed LHRH receptors. We could show that treatment of triple-negative but LHRH-positive MDA-MB-231, HCC1806 and HCC1937 human breast cancer cells with AEZS-108 (AN-152) resulted in apoptotic cell death in vitro via activation of caspase-3. The antitumor effects were confirmed in nude mice. AEZS-108 (AN-152) inhibited the growth of xenotransplants of triple-negative human breast cancers in nude mice completely, without any apparent side effects. The cytotoxic LHRH agonist AEZS-108 (AN-152) seems to be a suitable drug for an efficacious therapy for triple-negative breast cancers with little toxicity.
三阴性乳腺癌不表达雌激素和孕激素受体，也没有 HER2-neu 基因的过度表达/扩增。因此，这种乳腺癌亚型缺乏针对这些受体的特定治疗方法的益处。大约 60%的人类乳腺癌表达黄体生成素释放激素（LHRH，GnRH）受体，这些受体可以作为靶点。LHRH 受体可用于使用细胞毒性黄体生成素释放激素激动剂（如 AEZS-108[AN-152]）进行靶向化疗，其中阿霉素与[D-Lys6]LHRH 连接。在本研究中，我们通过体外和体内实验分析了表达 LHRH 受体的三阴性人乳腺癌细胞中细胞毒性 LHRH 激动剂 AEZS-108（AN-152）是否诱导细胞凋亡。使用免疫组织化学检测三阴性乳腺癌肿瘤活检标本中的 LHRH 受体表达。使用 alamar blue 增殖测定法分析细胞增殖。通过测量线粒体膜电位的丧失来量化诱导的细胞凋亡。使用携带人乳腺癌异种移植物的裸鼠进行体内实验。在 42 例三阴性乳腺癌中，有 31 例（73.8%）表达 LHRH 受体。我们可以证明，用 AEZS-108（AN-152）处理 LHRH 阳性的 MDA-MB-231、HCC1806 和 HCC1937 人乳腺癌细胞，会导致体外 caspase-3 的激活，从而导致细胞凋亡。在裸鼠中证实了抗肿瘤作用。AEZS-108（AN-152）完全抑制了裸鼠中三阴性人乳腺癌异种移植物的生长，没有任何明显的副作用。细胞毒性 LHRH 激动剂 AEZS-108（AN-152）似乎是一种适用于三阴性乳腺癌的有效治疗药物，毒性较小。
