On the other hand, change 6-OHDA-mediated ROS over-production or cell viability. All of these results indicate that ROS is important in mediating the cytotoxicity of 6-OHDA. Luteolin has the catechol LDN-57444 moiety, which can be oxidized during antioxidant reaction yielding o-quinone and may thus interfere with the cell signaling caused by p-quinone, and so exhibit higher cytoprotective efficacy than tiron. We further found that 6-OHDA treatment for 8 h successfully blocked the progression of cells from the S phase into the G2/M phase. In addition to formation of ROS, quinones are Michael acceptors, and cellular damage can occur through alkylation of crucial cellular proteins and DNA. The p53 tumor suppressor induces the transcription of genes that negatively regulate progression of the cell cycle in response to DNA damage. We found that 6-OHDA induced expression of p53 target genes, p21, GADD45a and PUMA, and the interaction with and dissociation of cyclin complexes may result in the cell cycle arrest that was observed in PC12 cells. This result supports an earlier report that 6-OHDA-induced DNA damage leads to the activation of the p53 DNA damage repair pathway, and p53-mediated PUMA upregulation leads to the induction of apoptosis. Pretreatment with luteolin reversed gene expression of p53 and its down-stream p21, GADD45a and PUMA, and therefore reduced cell cycle arrest and increased cell viability. Any chemical that induces ROS production or depletes glutathione has the potential to EPZ004777 hydrochloride induce ER stress and UPR, and there is growing evidence that 6-OHDA can cause ER stress in various cell types. In addition to ROS, arylating quinones induce ER stress by activating the PERK signaling pathway, including elF2a, ATF4, and CHOP. We found that 6-OHDA treatment alone activated one of the three canonical pathways of UPR, namely eIF2a-ATF4, suggesting that ER stress might be predominantly induced by Michael adduct formation by p-quinone. Stress conditions, such as ER stress, oxidative stress, amino acid deprivation and glucose starvation, induces both transcription and translation of ATF4.