Oxidants and Cell Death

在这些研究中，我们调查了氧化剂如何影响肿瘤进展，重点是氧化剂是否调节了抗肿瘤药物和肿瘤相关巨噬细胞对肿瘤细胞的清除。大多数化疗药物通过诱导细胞凋亡来杀死肿瘤细胞。实体瘤常常被炎性吞噬细胞渗透，在肿瘤组织内产生氧化应激。此前，我们发现在过氧化氢存在的情况下，人B淋巴瘤细胞无法发生凋亡，而是以坏死的形式死亡。自那以后，我们发现过氧化氢可以抑制多种化疗药物诱导的细胞凋亡。大多数细胞仍然死亡，但它们死亡的速度更慢，一些细胞完全逃脱了细胞死亡。通过在实验方案中加入抗氧化剂，可以克服过氧化氢的影响。过氧化氢和化疗药物相互作用的最重要后果之一是，在共培养的巨噬细胞膜溶解之前，细胞不会被吞噬。这些发现首次证明，来自肿瘤内免疫细胞的氧化剂可以通过以下几种机制干扰癌症化疗：(1)它们降低化疗药物诱导的细胞死亡的程度；(2)它们将细胞死亡的主要形式从凋亡转化为坏死；(3)它们推迟邻近巨噬细胞对濒死细胞的吞噬，直到它们裂解并将部分内容释放到细胞外环境中。这可能会导致不受欢迎的炎症反应，从而使肿瘤细胞枯竭进一步复杂化。我们还证明，在治疗方案中加入抗氧化剂可以提高化疗的疗效。这一假说目前正在用动物模型进行研究。目前正在进行研究，以阐明过氧化氢的作用机制。我们已经确定，氧化剂不会通过直接灭活凋亡过程所需的caspase酶来发挥作用。相反，它们抑制了半胱氨酸氨基转移酶在上游的凋亡级联反应的激活。

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.