Oxidants and Cell Death

在这些研究中，我们研究了氧化剂如何影响肿瘤进展，重点关注氧化剂是否通过抗肿瘤药物和肿瘤相关巨噬细胞调节肿瘤细胞的消除。大多数化疗药物通过诱导细胞凋亡来杀死肿瘤细胞。实体瘤常被炎性吞噬细胞浸润，炎性吞噬细胞可在肿瘤组织内产生氧化应激。先前，我们发现在H2O2存在的情况下，人B淋巴瘤细胞不能进行凋亡，而是以坏死的形式死亡。我们已经发现H2O2可以抑制多种化疗药物诱导的细胞凋亡。大多数细胞仍然会死亡，但它们的死亡速度更慢，有些细胞完全逃脱了细胞死亡。H2O2的影响可以通过在实验方案中加入抗氧化剂来克服。H2O2与化疗药物相互作用的一个最重要的结果是，直到细胞膜被溶解后，细胞才被共培养的巨噬细胞吞噬。这些发现首次表明，来自肿瘤内免疫细胞的氧化剂可以通过几种机制干扰癌症化疗：(1)它们降低了化疗药物诱导的细胞死亡程度；(2)它们将细胞死亡的主要形式从凋亡转化为坏死；(3)它们延缓了邻近巨噬细胞对垂死细胞的吞噬作用，直到它们裂解并将其部分内容物释放到细胞外环境中。这可能会导致不良的炎症反应，从而使肿瘤细胞的消耗进一步复杂化。我们还证明，在治疗方案中加入抗氧化剂可能会提高化疗的疗效。这一假设目前正在用动物模型进行研究。对H2O2作用机制的研究正在进行中。我们已经确定，氧化剂不会通过直接灭活凋亡过程所需的半胱天冬酶来起作用。相反，它们抑制凋亡级联中上游半胱天冬酶的激活。

In these studies, we investigate how oxidants may affect tumor progression, focusing on whether oxidants modulate tumor cell elimination by anti-neoplastic drugs and tumor-associated macrophages. Most chemotherapeutic agents kill tumor cells by inducing apoptosis. Solid tumors are often infiltrated by inflammatory phagocytes which can generate oxidative stress within the tumor tissue. Previously, we found that in the presence of H2O2, human B lymphoma cells are unable to undergo apoptosis and die instead by a form of necrosis. We have since discovered that H2O2 inhibits induction of apoptosis by a variety of chemotherapy drugs. Most of the cells still die, but they do so more slowly, and some of the cells escape cell death altogether. The effects of H2O2 can be overcome by including antioxidants in the experimental protocol. One of the most important consequences of the interaction between H2O2 and the chemotherapy drugs is that the cells do not become phagocytosed by co-cultured macrophages until after their membranes have lysed. These findings demonstrate, for the first time, that oxidants derived from immune cells within a tumor can interfere with cancer chemotherapy by several mechanisms: (1) they decrease the degree of cell death induced by the chemotherapeutic drugs; (2) they convert the predominant form of cell death from apoptosis to necrosis; and (3) they delay phagocytosis of the dying cells by neighboring macrophages until after they have lysed and released some of their contents into the extracellular milieu. This can lead to an undesirable inflammatory reaction which can further complicate tumor cell depletion. We also demonstrated that the efficacy of chemotherapy might be improved by including anti-oxidants in the treatment protocol. This hypothesis is currently being investigated with an animal model. Studies are ongoing to elucidate the mechanism of action of H2O2. We have determined that the oxidant does not act by directly inactivating the caspase enzymes that are required for the apoptotic process. Rather, they inhibit activation of caspases upstream in the apoptotic cascade.