Details

Autor(en) / Beteiligte

• Alexandre, Jérôme
• Batteux, Frédéric
• Nicco, Carole
• Chéreau, Christiane
• Laurent, Alexis
• Guillevin, Loïc
• Weill, Bernard
• Goldwasser, François

Titel

Accumulation of hydrogen peroxide is an early and crucial step for paclitaxel‐induced cancer cell death both in vitro and in vivo

Ist Teil von

• International journal of cancer, 2006-07, Vol.119 (1), p.41-48

Ort / Verlag

Hoboken: Wiley Subscription Services, Inc., A Wiley Company

Erscheinungsjahr

2006

Link zum Volltext

Quelle

Wiley Online Library All Journals

Beschreibungen/Notizen

• Intracellular events following paclitaxel binding to microtubules that lead to cell death remain poorly understood. Because reactive oxygen species (ROS) are involved in the cytotoxicity of anticancer agents acting through independent molecular targets, we explored the role of ROS in paclitaxel cytotoxicity. Within 15 min after in vitro exposure of A549 human lung cancer cells to paclitaxel, a concentration‐dependent intracellular increase in O°2− and H2O2 levels was detected by spectrofluorometry. Addition of N‐acetylcysteine (NAC) or glutathione, two H2O2 scavenger, induced a 4‐fold increase in paclitaxel IC50. Delaying NAC co‐incubation by 4 hr, resulted in a 3‐fold reduction in cell protection. The glutathione synthesis inhibitor, buthionine sulfoximine significantly increased paclitaxel cytotoxicity and H2O2 accumulation, but did not modify O°2− levels. Co‐incubation with diphenylene iodonium suggested that paclitaxel induced‐O°2− production was in part associated with increased activity of cytoplasmic NADPH oxidase. Concomitant treatment with inhibitors of caspases 3 and 8 increased cell survival but did not prevent the early accumulation of H2O2. To evaluate the role of ROS in paclitaxel antitumoral activity, mice were injected with LLC1 lung cancer cells and treated with paclitaxel i.p. and/or NAC. The antitumoral activity of paclitaxel in mice was abolished by NAC. In conclusion, the accumulation of H2O2 is an early and crucial step for paclitaxel‐induced cancer cell death before the commitment of the cells into apoptosis. These results suggest that ROS participate in vitro and in vivo to paclitaxel cytotoxicity. © 2006 Wiley‐Liss, Inc.