Oxidative stress interferes with cancer chemotherapy: inhibition of lymphoma cell apoptosis and phagocytosis.
Many antineoplastic drugs kill tumor cells by inducing apoptosis. This highly controlled mechanism of cell death is thought to be physiologically advantageous because apoptotic cells are removed by phagocytosis before they lose their permeability barrier, thus preventing induction of an inflammatory response to the dying cells. In contrast, necrotic cells lyse and release their contents into the extracellular space, thus inducing inflammation. In this report, we examine the effects of oxidative stress on chemotherapy-induced cell killing. We find that H(2)O(2) inhibits the ability of 4 different chemotherapy drugs (VP-16, doxorubicin, cisplatin, and AraC) to induce apoptosis in human Burkitt lymphoma cells. H(2)O(2) shifts the form of cell death from apoptosis to pyknosis/necrosis, which occurs after a significant delay compared with chemotherapy-induced apoptosis. It can also lower the degree of cell killing by these drugs. These effects of H(2)O(2) can be prevented by the antioxidant agents Desferal, Tempol, and dimethylsulfoxide. Phagocytosis by monocyte-derived macrophages of VP-16-treated lymphoma cells is also inhibited by H(2)O(2). Cells killed with H(2)O(2) (with or without VP-16) do ultimately undergo phagocytosis, but this occurs only after they have lost their permeability barrier. Thus, membrane-intact apoptotic cells are recognized and phagocytosed by monocyte-derived macrophages, but membrane-intact pyknotic/necrotic cells are not. The results suggest that chemotherapy-induced apoptosis and phagocytosis of cancer cells may be enhanced by including certain antioxidant agents in the treatment protocol.
Shacter
E
E
Laboratory of Immunology, Division of Therapeutic Proteins, Center for Biologics Evaluation and Research, Food and Drug Administration, Bethesda, MD, USA. shacter@cber.fda.gov
Williams
J A
JA
Hinson
R M
RM
Sentürker
S
S
Lee
Y J
YJ
D000970:Antineoplastic Agents / Q000633:toxicity*; D017209:Apoptosis / Q000187:drug effects*; D002051:Burkitt Lymphoma / Q000473:pathology; D002463:Cell Membrane Permeability; D002467:Cell Nucleus / Q000187:drug effects / Q000473:pathology; D002945:Cisplatin / Q000633:toxicity; D003561:Cytarabine / Q000633:toxicity; D004317:Doxorubicin / Q000633:toxicity; D005047:Etoposide / Q000633:toxicity; D006801:Humans; D006861:Hydrogen Peroxide / Q000633:toxicity*; D007700:Kinetics; D018384:Oxidative Stress / Q000187:drug effects; D010587:Phagocytosis / Q000187:drug effects*; D014407:Tumor Cells, Cultured
D000970:Antineoplastic Agents; D003561:Cytarabine; D005047:Etoposide; D004317:Doxorubicin; D006861:Hydrogen Peroxide; D002945:Cisplatin