Abstract
The natural product 23-hydroxyursolic acid (23-HUA) is a derivative of ursolic acid, which is known to induce cancer cell apoptosis. However, apoptotic effects and mechanisms of 23-HUA have not been well characterized yet. Herein, we investigated the molecular mechanisms of 23-HUA-induced apoptosis in HL-60 human promyelocytic leukemia cells. 23-HUA-treated HL-60 cells showed apoptotic features including internucleosomal DNA condensation and fragmentation as well as externalization of phosphatidylserine residues. 23-HUA induced a series of mitochondrial events including disruption of mitochondrial membrane potential (ΔΨm), cytochrome c and Smac/DIABLO release and loss of balance between pro-apoptotic and anti-apoptotic Bcl-2 proteins in HL-60 cells. In addition, 23-HUA activated caspase-8, caspase-9 and caspase-3. Pretreatment with a broad caspase inhibitor (z-VAD-fmk), a caspase-3 inhibitor (z-DEVD-fmk), and a caspase-8 inhibitor (z-IETD-fmk) significantly attenuated 23-HUA-induced DNA fragmentation. After 23-HUA-induced apoptosis, proteins expression levels of FasL, Fas and FADD constituting the death-inducing signaling complex (DISC) were upregulated in HL-60 cells. Moreover, transfection with Fas or FADD siRNA significantly blocked 23-HUA-induced DNA fragmentation and caspases activation. Taken together, these findings indicate that 23-HUA induces apoptosis in HL-60 human promyelocytic leukemia cells through formation of DISC and caspase-8 activation leading to loss of ΔΨm and caspase-3 activation.
Highlights
Apoptosis is a programmed cell death triggered by many chemotherapeutic agents within leukemic cells [1]
We have found that 23-hydroxyursolic acid (23-HUA) inhibited cell growth via induction of caspase-dependent apoptosis in human HeLa cells [19]
No significant changesininloss of control cells. These results suggest that truncated Bid (tBid) and Bax could directly bind to Bcl-2 resulting expression of other Bcl-2between family proteins
Summary
Apoptosis is a programmed cell death triggered by many chemotherapeutic agents within leukemic cells [1]. Fas-associated death domain (FADD) and procaspase-8 to form DISC that induces autocatalytic cleavage of procaspase-8 leading to caspase-8 activation. Some triterpenoids have been found to elicit selective cytotoxicity against cancer cells rather than normal cells [10,11,12]. The ursane-type pentacyclic ursolic acid (3β-hydroxyurs-12-en-28-oic-acid, Figure 1) has been reported to elicit in vitro and in vivo bioactivity against cancer models [13,14,15]. We investigated molecular mechanism involved the cytotoxic properties of 23-HUA through the formation of DISC by Fas-FasL binding and activation of caspase cascade in HL-60 leukemia cells
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