Formaldehyde and Cancer Pain Figure 6. Inhibition of formaldehyde scavengers on formaldehyde-induced neurotoxicity. (A) Formaldehyde (FA) decreased cell viability of the cultured DRG neurons with a dose-dependent manner. (B) Chemical reaction of formaldehyde with resveratrol and glutathione. (C) Resveratrol (Res) and (D) glutathione (GSH) inhibition on the formaldehyde-induced cell viability decrease. * p,0.05, ** p,0.01, # p,0.05, ## p,0.01. n = 6. doi:10.1371/journal.pone.0010234.g006 intracellular endogenous formaldehyde [60]. This may be the mechanism by which resveratrol defends against all kinds of cancer [61]. A previous study showed that the level of glutathione was significantly decreased in the blood of patients with breast cancer [62]. Moreover, by conferring resistance to a number of chemotherapeutic drugs, elevated levels of glutathione in tumor cells are able to protect these cells in bone marrow, breast, colon, larynx and lung cancers [63]. Both resveratrol and glutathione compounds are antioxidants. Interestingly both TRPA1 and TRPV1 are activated by oxidative stress [64,65]. The antioxidant effect of resveratrol and glutathione may partially prevent oxidative stress-induced pain. In summary, the present study indicates that accelerated acidification and chronically accumulated formaldehyde which are derived from local cancer tissues synergistically stimulate nerve fiber endings and lead to bone cancer pain. Use of formaldehyde scavengers may be a novel therapeutic approach for treatment of bone cancer pain. Materials and Methods Ethics statement All experiments involving animals were conducted with the approval of the Peking University Animal Care and Use Committee. Informed consent was obtained for all participants and written by themselves. All the clinical investigation was performed after approval by the Ethics Committee of Peking University Health Science Center. Cancer tissues from patients suffered from bone cancer pain after clinic pain assessment In all cases, bone cancer pain was indicated based upon clinical diagnosis. A questionnaire which included a diagram to indicate painful and tender areas and the pain descriptors from the McGill Pain Questionnaire were produced, along with a 10-cm unmarked visual analogue scale (VAS), and VAS scores marked by the patient in centimeters being more than zero to identify those PLoS ONE | www.plosone.org 10 April 2010 | Volume 5 | Issue 4 | e10234