Abstract
The aim of this study was to investigate the mechanism of flavonoid-induced apoptosis
in HL-60 leukaemic cells. Thus, the effect of structurally related flavonoids on cell
viability, DNA fragmentation and caspase activity was assessed. Loss of membrane potential
and reactive oxygen species generation were also monitored by flow cytometry. The
structurally related flavonoids, such as apigenin, quercetin, myricetin, and kaempferol
were able to induce apoptosis in human leukaemia HL-60 cells. Treatment with flavonoids
(60 μM) caused a rapid induction of caspase-3 activity and stimulated proteolytic cleavage
of poly-(ADP-ribose) polymerase (PARP). Furthermore, these flavonoids induced loss
of mitochondrial transmembrane potential, elevation of reactive oxygen species (ROS)
production, release of mitochondrial cytochrome c into the cytosol, and subsequent
induction of procaspase-9 processing. The potency of these flavonoids on these features
of apoptosis were in the order of: apigenin>quercetin>myricetin>kaempferol in HL-60
cells treated with 60 μM flavonoids. These results suggest that flavonoid-induced apoptosis is stimulated
by the release of cytochrome c to the cytosol, by procaspase-9 processing, and through
a caspase-3-dependent mechanism. The induction of apoptosis by flavonoids may be attributed
to their cancer chemopreventive activity. Furthermore, the potency of flavonoids for
inducing apoptosis may be dependent on the numbers of hydroxyl groups in the 2-phenyl
group and on the absence of the 3-hydroxyl group. This provides new information on
the structure–activity relationship of flavonoids.
Keywords
To read this article in full you will need to make a payment
Purchase one-time access:
Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online accessOne-time access price info
- For academic or personal research use, select 'Academic and Personal'
- For corporate R&D use, select 'Corporate R&D Professionals'
Subscribe:
Subscribe to European Journal of CancerAlready a print subscriber? Claim online access
Already an online subscriber? Sign in
Register: Create an account
Institutional Access: Sign in to ScienceDirect
References
- Toxicity and carcinogenicity studies of quercetin, a natural component of foods.Fund Appl. Toxicol. 1992; 19: 423-431
- Naturally occurring anticarcinogenic substances in foodstuffs.Ann. Rev. Nutrit. 1985; 5: 295-321
- Relative bioavailability of the antioxidant flavonoid quercetin from various foods in man.FEBS Lett. 1997; 418: 152-156
- study of flavone acetic acid (NSC 347512, LM975) in patients with pediatric malignant solid tumors.Am. J. Clin. Oncol. 1991; 14: 483-486
- Inhibitions of protein kinase c and proto-oncogene expressions in NIH 3T3 cells by apigenin.Eur. J. Cancer. 1996; 32A: 146-151
- Apoptosis: a basic biological phenomenon with wide-ranging implications in tissue kinetics.Br. J. Cancer. 1972; 26: 239-257
- Zinc inhibits UV radiation-induced apoptosis but fails to prevent subsequent cell death.Int. J. Radiat. Biol. 1994; 66: 343-349
- Lymphocyte apoptosis induced by CD95 (APO-1/Fas) ligand-expressing tumour cells—a mechanism of immune evasion?.Nature Med. 1996; 2: 1361-1366
- Apoptosis by a cytosolic extract from Fas-activated cells.EMBO J. 1995; 14: 5201-5208
- Drug–target interactions: only the first step in the commitment to a programmed cell death?.Br. J. Cancer. 1991; 64: 192-196
- Induction of internucleosomal DNA fragmentation in human myeloid leukemia cells by 1-beta-d-arabinofuranosylcytosine.Cancer Res. 1991; 51: 741-743
- The induction of apoptosis by chemotherapeutic agents occurs in all phases of the cell cycle.Anticancer Res. 1992; 12: 773-779
- Protease activation during apoptosis: death by a thousand cuts?.Cell. 1995; 82: 349-352
- Apoptosis by death factor.Cell. 1997; 88: 355-365
- Cleavage of lamin A by Mch2 alpha but not CPP32: multiple interleukin 1 beta-converting enzyme-related proteases with distinct substrate recognition properties are active in apoptosis.Proc. Natl. Acad. Sci. USA. 1996; 93: 8395-8400
- A novel human protease similar to the interleukin-1 beta converting enzyme induces apoptosis in transfected cells.EMBO J. 1995; 14: 1914-1922
- Yama/CPP32 beta, a mammalian homolog of CED-3, is a CrmA-inhibitable protease that cleaves the death substrate poly(ADP-ribose) polymerase.Cell. 1995; 81: 801-809
- Prevention of apoptosis by Bcl-2: release of cytochrome c from mitochondria blocked.Science. 1997; 275: 1129-1132
- The release of cytochrome c from mitochondria: a primary site for bcl-2 regulation of apoptosis.Science. 1997; 275: 1132-1136
- domain: a new apoptotic signaling motif.Trends Biochem. Sci. 1997; 22: 155-156
- Cytochrome c and dATP-dependent formation of Apaf-1/Caspase-9 complex initiates an apoptotic protease cascade.Cell. 1997; 91: 479-489
- Composition of polyphenols in fresh tea leaves and associations of their oxygen-radical-absorbing capacity with antiproliferative actions in fibroblast cells.J. Agric. Food Chem. 1996; 44: 1387-1394
- Molecular mechanisms in the antiproliferative action of quercetin.Life Sci. 1997; 60: 2157-2163
- Induction of p21/WAF1 and G1 cell-cycle arrest by the chemopreventive agent apigenin.Molec. Carcinogen. 1997; 19: 74-82
- Studies on the inhibitory effects of quercetin on the growth of HL-60 leukemia cells.Biochem Pharmacol. 1997; 54: 1013-1018
- Induction of apoptosis by quercetin: involvement of heat shock protein.Cancer Res. 1994; 54: 4952-4957
- Flavonoids activate wild-type p53.Oncogene. 1996; 13: 1605-1614
- Cytochrome c: can't live with it—can't without it.Cell. 1997; 91: 559-562
Middleton E Jr, Kandaswami C. The impact of plant flavonoids on mammalian biology: implications for immunity, inflammation and cancer. In Harborne TH, Liss AR, eds. Flavonoids: Advances in Research Since 1986. New York, Chapman and Hall 1994, 619–625.
- Protein kinase C inhibition by plant flavonoids. Kinetic mechanisms and structure-activity relationships.Biochem. Pharmacol. 1989; 38: 1617-1624
- Inhibition of protein-tyrosine kinase activity by flavanoids and related compounds.J. Natl. Products. 1989; 52: 982-986
- Synthesis and protein-tyrosine kinase inhibitory activities of flavonoid analogues.J. Med. Chem. 1991; 34: 798-806
- Relationship between flavonoid structure and inhibition of phosphatidylinositol 3-kinase: a comparison with tyrosine kinase and protein kinase C inhibition.Biochem. Pharmacol. 1997; 53: 1649-1657
- Structural requirements for differentiation-induction and growth-inhibition of mouse erythroleukemia cells by isoflavones.Anticancer Res. 1995; 15: 1147-1152
- Radioprotective effect of antioxidative flavonoids in gamma-ray irradiated mice.Carcinogenesis. 1994; 15: 2669-2672
Article info
Publication history
Accepted:
July 13,
1999
Received:
June 30,
1999
Identification
Copyright
© 1999 Elsevier Science Ltd. Published by Elsevier Inc. All rights reserved.
