The outcome of producing apoptotic defects in
cancer cells is the primary obstacle that limits the therapeutic efficacy of
anticancer agents, and hence the development of novel agents targeting novel non-canonical cell death pathways has become an imperative mission for clinical research.
Fisetin (3,3',4',7-tetrahydroxyflavone) is a naturally occurring
flavonoid commonly found in fruits and vegetables. In this study, we investigated the potential anticancer effects of
fisetin on
breast cancer cells. The result showed
fisetin induced higher cytotoxicity in human
breast cancer MCF-7 than in MDA-MB-231 cells otherwise it did not exert any detectable cytotoxicity in non-tumorigenic MCF-10A cells. We found
fisetin can trigger a novel form of atypical apoptosis in caspase-3-deficient MCF-7 cells, which was characterized by several apoptotic features, including plasma membrane
rupture, mitochondrial depolarization, activation of
caspase-7, -8 and -9, and PARP cleavage; however, neither DNA fragmentation and phosphotidylserine (PS) externalization was observed. Although p53 was also activated by
fisetin, the
fisetin-induced apoptosis was not rescued by the p53 inhibitor
pifithrin-α. In contrast, the
fisetin-induced apoptosis was abrogated by pan-
caspase inhibitor
z-VAD-fmk. Furthermore, inhibition of autophagy by
fisetin was shown as additional route to prompt anticancer activity in MCF-7 cells. These data allow us to propose that
fisetin appears as a new potential
anticancer agent which can be applied to develop a clinical protocol of human breast
cancers.