Hexahydro-β-acids induce apoptosis through mitochondrial pathway, GADD153 expression, and caspase activation in human leukemia cells.
Hexahydro-β-acids (HBA) and β-acids (BA) displayed strong growth inhibitory effects against human leukemia HL-60 cells and were able to induce apoptosis in a concentration- and time-dependent manner and the morphological changes associated with apoptotic cell death; however, BA was less effective. Treatment with HBA caused a rapid loss of mitochondrial trans-membrane potential, release of mitochondrial cytochrome c into cytosol. The levels of Bad and Bax were dramatically increased in cells treated with HBA. In addition, the results showed that HBA promoted the up-regulation of Fas prior to the processing and activation of pro-caspase-8 and cleavage of Bid, suggesting the involvement of a Fas-mediated pathway in HBA-induced cells. Moreover, the changes occurred after single breaks in DNA were detected, suggesting that HBA induced irreparable DNA damage, which in turn triggered the process of apoptosis. HBA markedly enhanced the growth arrest DNA damage-inducible gene 153 (GADD153) protein in a concentration- and time-dependent manner. These findings suggest that HBA creates an oxidative cellular environment that induces DNA damage and GADD153 gene activation, which in turn triggers apoptosis in HL-60 cells. Our study identified the novel mechanisms of HBA-induced apoptosis and indicated that HBA may be used as a potential chemopreventive and chemotherapeutic agent.
Department of Seafood Science, National Kaohsiung Marine University, Kaohsiung 811, Taiwan.
Cheng Bin
CB
Liu
Li-Hua
LH
Chen
An-Chin
AC
Cheng
Wei-Jen
WJ
Chen
Mei-Ling
ML
Tsai
Yumei
Y
Liu
Chi-Tang
CT
Ho
Min-Hsiung
MH
Pan
D000143:Acids / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D020169:Caspases / Q000378:metabolism*; D002851:Chromatography, High Pressure Liquid; D004249:DNA Damage; D004789:Enzyme Activation; D018922:HL-60 Cells; D006801:Humans; D007938:Leukemia / Q000201:enzymology / Q000378:metabolism / Q000473:pathology*; D008928:Mitochondria / Q000187:drug effects* / Q000378:metabolism; D051742:Transcription Factor CHOP / Q000378:metabolism*
D000143:Acids; C497249:DDIT3 protein, human; D051742:Transcription Factor CHOP; D020169:Caspases