Web Release Date: December 16,
Mechanisms of Cancer Chemoprevention by Hop Bitter Acids (Beer Aroma) through Induction of Apoptosis Mediated by Fas and Caspase Cascades
Institute of Biochemistry and Molecular Biology, College of Medicine, National Taiwan University, Taipei, Taiwan
Received for review July 7, 2003. Revised manuscript received October 30, 2003. Accepted November 4, 2003. This study was supported by the National Science Council (NSC 91-2320-B-002-068 and NSC 91- 2311-B-002-037) and by the National Health Research Institute (NHRI-EX91-8913BL).
Abstract:
The bitter acids of hops (Humulus lupulus L.) mainly consist of 
-acids, 
-acids, and their oxidation
products that contribute the unique aroma of the beer beverage. Hop bitter acids displayed a strong
growth inhibitory effect against human leukemia HL-60 cells, with an estimated IC50 value of 8.67
g/mL, but were less effective against human histolytic lymphoma U937 cells. Induction of apoptosis
was confirmed in HL-60 cells by DNA fragmentation and the appearance of a sub-G1 DNA peak,
which were preceded by dissipation of mitochondrial membrane potential, cytochrome c release,
and subsequent induction of pro-caspase-9 and -3 processing. Cleavages of PARP and DFF-45
were accompanied with activation of caspase-9 and -3 triggered by hop bitter acids in HL-60 cells.
The change in the expression of Bcl-2, Bcl-XL, and Bax in response to hop bitter acids was studied,
and the Bcl-2 protein level slightly decreased; however, the Bcl-XL protein level was obviously
decreased, whereas the Bax protein level was dramatically increased, indicating that the control of
Bcl-2 family proteins by hop bitter acids might participate in the disruption of mitochondrial integrity.
In addition, the results showed that hop bitter acids promoted the up-regulation of Fas and FasL
prior to the processing and activation of pro-caspase-8 and cleavage of Bid, suggesting the involvement
of a Fas-mediated pathway in hop bitter acids-induced cells. Taken together, these findings suggest
that a certain intimate link might exist between receptor- and mitochondria-mediated death signalings
that committed to cell death induced by hop bitter acids. The induction of apoptosis by hop bitter
acids may offer a pivotal mechanism for their chemopreventive action.
Keywords: Hop bitter acids; -acids; -acids; apoptosis; caspase; mitochondria; Bcl-2; Bcl-XL; Bax;
Fas; FasL; Bid
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