Department of Pharmacology, Faculty of Pharmacy, University of Seville, Seville, Spain.
Planta Med. 2013 Aug;79(12):1017-23. doi: 10.1055/s-0032-1328715. Epub 2013 Jul 3.
Recent evidence suggests that cardiac glycosides might be used for the treatment of cancer. The ornamental shrub Nerium oleander has been used in traditional medicine for treating several disorders including cancer, and extracts from the leaves of this plant have already entered phase I clinical trials. In this communication, we have prepared a hydroalcoholic extract from the leaves of Nerium oleander (containing 4.75 ± 0.32 % of cardenolides) and have assessed its cytotoxic activity in A549 lung cancer cells vs. MRC5 nonmalignant lung fibroblasts. The results showed that the cytotoxicity of the Nerium oleander extract against the cancer cell line was significantly higher than that against the nonmalignant cell line, with a potency and selectivity similar to those of the anticancer drug cisplatin. Pretreatment of A549 cells with the antioxidants N-acetylcysteine and catalase slightly prevented the cytotoxicity of the extract, therefore suggesting that the formation of reactive oxygen species participates in its cytotoxic activity but does not play a major role. Nerium oleander extract-induced cytotoxicity and DNA damage (gamma-H2AX focus formation) were slightly higher in cells lacking BRCA2 (deficient in homologous recombination repair) than in parental cells; this indicates that the induction of DNA damage may also play a role in the cytotoxicity of the extract. Nerium oleander extract induced a marked inhibition of glycolysis (glucose consumption and lactate production) in A549 cells, comparable to that of the glycolysis inhibitor dichloroacetate (currently in clinical development for cancer therapy). Because platinum compounds are widely used in the treatment of lung cancer, we tested the cytotoxicity of several combinations of cisplatin with the extract and found a moderate synergism when Nerium oleander extract was administered after cisplatin but a moderate antagonism when it was added before cisplatin. Our results suggest that extracts from Nerium oleander might induce anticancer effects in patients with lung cancer and support their possible advancement into phase II clinical trials for the treatment of this type of cancer.
最近的证据表明，强心苷类药物可能用于治疗癌症。观赏灌木夹竹桃已在传统医学中用于治疗多种疾病，包括癌症，并且该植物的叶提取物已进入 I 期临床试验。在本通讯中，我们从夹竹桃的叶中制备了一种水醇提取物（含有 4.75 ± 0.32％的强心苷），并评估了其在 A549 肺癌细胞与 MRC5 非恶性肺成纤维细胞中的细胞毒性活性。结果表明，夹竹桃提取物对癌细胞系的细胞毒性明显高于对非恶性细胞系的细胞毒性，其效力和选择性与抗癌药物顺铂相似。用抗氧化剂 N-乙酰半胱氨酸和过氧化氢酶预处理 A549 细胞可轻微预防提取物的细胞毒性，因此表明活性氧的形成参与了其细胞毒性活性，但不起主要作用。BRCA2 缺失（同源重组修复缺陷）的细胞中，夹竹桃提取物诱导的细胞毒性和 DNA 损伤（γ-H2AX 焦点形成）略高于亲本细胞；这表明 DNA 损伤的诱导也可能在提取物的细胞毒性中起作用。夹竹桃提取物可明显抑制 A549 细胞的糖酵解（葡萄糖消耗和乳酸产生），与糖酵解抑制剂二氯乙酸（目前正在临床开发用于癌症治疗）相当。由于铂化合物广泛用于治疗肺癌，我们测试了几种顺铂与提取物组合的细胞毒性，发现当在顺铂后给予夹竹桃提取物时具有适度的协同作用，而当在顺铂前给予时具有适度的拮抗作用。我们的结果表明，夹竹桃提取物可能在肺癌患者中诱导抗癌作用，并支持它们可能进入 II 期临床试验以治疗这种类型的癌症。
