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

Abstract

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°2 and H 2 O 2 levels was detected by spectrofluorometry. Addition of N-acetylcysteine (NAC) or glutathione, two H 2 O 2 scavenger, induced a 4-fold increase in paclitaxel IC 50 . 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 H 2 O 2 accumulation, but did not modify O 2°2 levels. Co-incubation with diphenylene iodonium suggested that paclitaxel induced-O 2°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 H 2 O 2. 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 H 2 O 2 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.

Amplification of oxidative stress by a dual stimuli-responsive hybrid drug enhances cancer cell death

“…Ironically, cancer cells are also known to utilize ROS to drive proliferation and other events required for tumour development 11,12 . However, the high level of ROS can cause cellular damage and apoptotic cell death, depending on the concentration and duration of ROS stress 13 . Cancer cells are also susceptible to further ROS insults induced by exogenous agents that weaken antioxidant defense or augment ROS generation to a level or the threshold above which cells cannot survive [14][15][16] .…”

Transient Receptor Potential Channels in Chemotherapy-Induced Neuropathy

“…Recent evidence has proposed a role for TRPV4 in mechanical allodynia in rodent models of CIPN [101][102][103]. In different models of painful peripheral neuropathy, mechanical hyperalgesia was markedly reduced by spinal intrathecal administration of oligodeoxynucleotides antisense to TRPV4 [74].…”

Regional localisation of p53-independent apoptosis determines toxicity to 5-fluorouracil and pyrrolidinedithiocarbamate in the murine gut

“…Reactive oxygen species generation has been demonstrated in a range of tumours 6 -48 h after treatment with various anticancer agents (Ikeda et al, 1999;Huang et al, 2003;Fawcett et al, 2005;Rahmani et al, 2005). Indeed, the antitumour activity of paclitaxel in mice was abolished by NAC as accumulation of H 2 O 2 is an early and crucial step for paclitaxel-induced cancer cell death (Alexandre et al, 2006a).…”