Mitchell Cancer Institute, University of South Alabama, Mobile, Alabama, USA.
Mol Cancer. 2010 Feb 9;9:33. doi: 10.1186/1476-4598-9-33.
Taxol is one of the most effective chemotherapeutic agents for the treatment of patients with breast cancer. Despite impressive clinical responses initially, the majority of patients eventually develop resistance to Taxol. Lactate dehydrogenase-A (LDH-A) is one of the predominant isoforms of LDH expressed in breast tissue, which controls the conversion of pyruvate to lactate and plays an important role in glucose metabolism. In this study we investigated the role of LDH-A in mediating Taxol resistance in human breast cancer cells.
Taxol-resistant subclones, derived from the cancer cell line MDA-MB-435, sustained continuous growth in high concentrations of Taxol while the Taxol-sensitive cells could not. The increased expression and activity of LDH-A were detected in Taxol-resistant cells when compared with their parental cells. The downregulation of LDH-A by siRNA significantly increased the sensitivity of Taxol-resistant cells to Taxol. A higher sensitivity to the specific LDH inhibitor, oxamate, was found in the Taxol-resistant cells. Furthermore, treating cells with the combination of Taxol and oxamate showed a synergistical inhibitory effect on Taxol-resistant breast cancer cells by promoting apoptosis in these cells.
LDH-A plays an important role in Taxol resistance and inhibition of LDH-A re-sensitizes Taxol-resistant cells to Taxol. This supports that Warburg effect is a property of Taxol resistant cancer cells and may play an important role in the development of Taxol resistance. To our knowledge, this is the first report showing that the increased expression of LDH-A plays an important role in Taxol resistance of human breast cancer cells. This study provides valuable information for the future development and use of targeted therapies, such as oxamate, for the treatment of patients with Taxol-resistant breast cancer.
紫杉醇是治疗乳腺癌患者最有效的化疗药物之一。尽管最初的临床反应令人印象深刻，但大多数患者最终还是会对紫杉醇产生耐药性。乳酸脱氢酶-A（LDH-A）是在乳腺组织中表达的主要 LDH 同工酶之一，它控制着丙酮酸向乳酸的转化，在葡萄糖代谢中发挥着重要作用。在这项研究中，我们研究了 LDH-A 在介导人乳腺癌细胞对紫杉醇耐药中的作用。
从 MDA-MB-435 癌细胞系中获得的紫杉醇耐药亚克隆在高浓度紫杉醇中持续不断地生长，而紫杉醇敏感细胞则不能。与亲本细胞相比，在紫杉醇耐药细胞中检测到 LDH-A 的表达和活性增加。用 siRNA 下调 LDH-A 显著增加了紫杉醇耐药细胞对紫杉醇的敏感性。在紫杉醇耐药细胞中发现对特定的 LDH 抑制剂氧甲酸盐的敏感性更高。此外，用紫杉醇和氧甲酸盐联合处理细胞，通过促进这些细胞的凋亡，对紫杉醇耐药乳腺癌细胞表现出协同抑制作用。
LDH-A 在紫杉醇耐药中起重要作用，抑制 LDH-A 可使紫杉醇耐药细胞重新对紫杉醇敏感。这支持了沃伯格效应是紫杉醇耐药癌细胞的一个特性，并且可能在紫杉醇耐药的发展中起重要作用。据我们所知，这是第一个表明 LDH-A 表达增加在人乳腺癌细胞紫杉醇耐药中起重要作用的报告。这项研究为未来开发靶向治疗提供了有价值的信息，例如氧甲酸盐，用于治疗紫杉醇耐药的乳腺癌患者。
