Intrinsic oxidative stress in cancer cells: a biochemical basis for therapeutic selectivity
Intrinsic oxidative stress in cancer cells: a biochemical basis for therapeutic selectivity
复制标题
DOI：
10.1007/s00280-003-0726-5
复制
发表时间：
2004-03-01
影响因子：
3
通讯作者：
Huang, P
中科院分区：
文献类型：
--
作者：
Hileman, EO;Liu, JS;Huang, P
目的。治疗选择性是癌症化疗中最重要的考虑因素之一。优先杀死恶性细胞同时最大限度地减少对正常细胞的有害影响的治疗策略的设计取决于我们对癌症和正常细胞之间生物学差异的理解。我们之前已经证明，某些产生活性氧（ROS）的药物，例如2-甲氧基雌二醇（2-ME），会优先杀死人类白血病细胞，而不会在正常淋巴细胞中表现出明显的细胞毒性。本研究的目的是调查这种选择性抗癌活性的生化基础。方法。流式细胞术分析用于测量细胞内O-2(-)水平和细胞凋亡。 MTT 测定被用作细胞活力的指标。蛋白质印迹分析用于测量癌症和正常细胞中抗氧化酶的表达。结果。一般来说，恶性细胞在产生 O-2(-) 方面比正常细胞更活跃，处于内在氧化应激之下，因此更容易受到 ROS 生成剂的损害。癌细胞中的内在氧化应激与 SOD 和过氧化氢酶蛋白表达的上调有关，可能是耐受 ROS 应激增加的机制。在原代人白血病细胞和原代卵巢癌细胞中均观察到 SOD 和过氧化氢酶表达的增加。两种恶性细胞类型都比正常细胞对 2-ME 更敏感，O-2(-) 的显着积累和随后的细胞凋亡证明了这一点。 ROS 清除剂与 2-ME 联合使用可防止 O-2(-) 的积累并消除细胞凋亡诱导。结论。 O-2(-)是2-ME诱导细胞凋亡的重要介质。癌细胞中氧化应激的增加迫使这些细胞更多地依赖抗氧化酶如SOD来消除O-2(-)，从而使恶性细胞比正常细胞更容易受到SOD抑制。
Purpose. Therapeutic selectivity is one of the most important considerations in cancer chemotherapy. The design of therapeutic strategies to preferentially kill malignant cells while minimizing harmful effects to normal cells depends on our understanding of the biological differences between cancer and normal cells. We have previously demonstrated that certain agents generating reactive oxygen species (ROS) such as 2-methoxyestradiol (2-ME) preferentially kill human leukemia cells without exhibiting significant cytotoxicity in normal lymphocytes. The purpose of the current study was to investigate the biochemical basis for such selective anticancer activity.Methods. Flow cytometric analyses were utilized to measure intracellular O-2(-) levels and apoptosis. MTT assays were used as indicators of cellular viability. Western blot analysis was used to measure the expression of antioxidant enzymes in cancer and normal cells. Results. Malignant cells in general are more active than normal cells in the production of O-2(-), are under intrinsic oxidative stress, and thus are more vulnerable to damage by ROS-generating agents. The intrinsic oxidative stress in cancer cells was associated with the upregulation of SOD and catalase protein expression, likely as a mechanism to tolerate increased ROS stress. The increase in SOD and catalase expression was observed both in primary human leukemia cells and in primary ovarian cancer cells. Both malignant cell types were more sensitive to 2-ME than their normal counterparts, as demonstrated by the significant accumulation of O-2(-) and subsequent apoptosis. The administration of ROS scavengers in combination with 2-ME prevented the accumulation of O-2(-) and abrogated apoptosis induction. Conclusions. O-2(-) is an important mediator of 2-ME-induced apoptosis. The increased oxidative stress in cancer cells forces these cells to rely more on antioxidant enzymes such as SOD for O-2(-) elimination, thus making the malignant cells more vulnerable to SOD inhibition than normal cells.