Vanillin derivative 6-bromine-5-hydroxy-4-methoxybenzaldehyde-elicited apoptosis and G2/M arrest of Jurkat cells proceeds concurrently with DNA-PKcs cleavage and Akt inactivation.
Vanillin, a naturally occurring food component, has been reported to have anti-mutagenic and anti-metastatic potentials, and to inhibit DNA-PKcs activity. However, vanillin itself exhibits very weak antiproliferative activity. We explored the effects of bromovanin (6-bromine-5-hydroxy-4-methoxybenzaldehyde), a novel vanillin derivative, on survival and cell-cycle progression of human Jurkat leukemia cells. Treatment with >10 microM bromovanin significantly elicited apoptosis and G2/M arrest in Jurkat cells in a dose- and time-dependent manner. Bromovanin-induced DNA double-strand breaks (DSB) were demonstrated by means of comet assay as well as detection of phosphorylated H2AX, a sensitive indicator of DNA DSBs. Immuno-hybridization analysis revealed that the cleavage of procaspase-3 and DNA-PKcs occurred concurrently with bromovanin-induced apoptosis. Furthermore, phosphorylated Akt protein (Ser473), which is catalyzed by DNA-PKcs, as well as phosphorylated GSK3beta (a substrate of activated Akt), markedly decreased in bromovanin-treated Jurkat cells, suggesting that bromovanin leads to inactivation of Akt pathway via cleaving DNA-PKcs. These multiple effects, associated with the regimen of cancer therapeutic strategies, make bromovanin very appealing for future development as a novel anticancer drug.
Yan
Yu-Qian
YQ
Department of Radiation Toxicology and Oncology, Beijing Institute of Radiation Medicine, Beijing 100850, P.R. China.
Xu
Qin-Zhi
QZ
Wang
Lin
L
Sui
Jian-Li
JL
Bai
Bei
B
Zhou
Ping-Kun
PK
D017209:Apoptosis; D001547:Benzaldehydes / Q000737:chemistry* / Q000494:pharmacology*; D002453:Cell Cycle / Q000187:drug effects; D004247:DNA / Q000187:drug effects; D004249:DNA Damage; D051747:DNA-Activated Protein Kinase / Q000187:drug effects*; D006801:Humans; D019169:Jurkat Cells; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors*
D001547:Benzaldehydes; C515564:bromovanin; D004247:DNA; C100058:vanillin; D051747:DNA-Activated Protein Kinase; D051057:Proto-Oncogene Proteins c-akt