Journal
AMERICAN JOURNAL OF CHINESE MEDICINE
Volume 47, Issue 4, Pages 841-863Publisher
WORLD SCIENTIFIC PUBL CO PTE LTD
DOI: 10.1142/S0192415X19500447
Keywords
Fisetin; Cell Cycle; G(0)/G(1) Phase Arrest; Apoptosis; WEHI-3 Cells; Leukemia
Funding
- Asia University [ASIA104-CMUH-04]
- China Medical University Hospital (Taiwan)
- Ministry of Science and Technology of Taiwan [MOST 106-2320-B-039-011]
- China Medical University Hospital (Taiwan) [DMR-107-135, DMR-107-136]
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Fisetin, a naturally occurring flavonoid, is found in common fruits and vegetables and has been shown to induce cytotoxic effects in many human cancer cell lines. No information has shown that fisetin induced cell cycle arrest and apoptosis in mouse leukemia WEHI-3 cells. We found that fisetin decreased total viable cells through G(0)/G(1) phase arrest and induced sub-G(1) phase (apoptosis). We have confirmed fisetin induced cell apoptosis by the formation of DNA fragmentation and induction of apoptotic cell death. Results indicated that fisetin induced intracellular Ca2+ increase but decreased the ROS production and the levels of Delta Psi m in WEHI-3 cells. Fisetin increased the activities of caspase-3, -8 and -9. Cells were pre-treated with inhibitors of caspase-3, -8 and -9 and then treated with fisetin and results showed increased viable cell number when compared to fisetin treated only. Fisetin reduced expressions of cdc25a but increased p-p53, Chk1, p21 and p27 that may lead to G(0)/G(1) phase arrest. Fisetin inhibited anti-apoptotic protein Bcl-2 and Bcl-xL and increased pro-apoptotic protein Bax and Bak. Furthermore, fisetin increased the protein expression of cytochrome c and AIF. Fisetin decreased cell number through G(0)/G(1) phase arrest via the inhibition of cdc25c and induction of apoptosis through caspase-dependent and mitochondria-dependent pathways. Therefore, fisetin may be useful as a potential therapeutic agent for leukemia.
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