other player(s) mediate(s) the apoptotic event downstream of cytochrome c at the post-mitochondrial level. A somewhat different setting but relevant finding has been reported previously [34]. Zhou et al. investigated how Akt regulates hybrid motor neuron 1 cells, a neuronal cell line that requires PI 3-kinase/Akt for survival [34]. They found that Akt inhibits cell death and cytochrome c-induced caspase activation without blocking the release of cytochrome c, suggesting that Akt regulates the suppression of the neural apoptosis at a post-mitochondrial stage, downstream of cytochrome c release, and before activating caspase-9 [34].

Together, our data indicated that PDTC inhibited luteolin-induced apoptosis in both extrinsic and intrinsic pathways (Figure 6), potentially modulated by Akt. Further studies deem necessary to elucidate the regulatory roles of Akt in the combining effect of luteolin and PDTC between the dynamics of apoptosis and cell survival. The combination of luteolin and PDTC increased the survival of the cancer cells rather than reduced the cell number in HL-60 cells. This finding may have clinical implication that the therapeutic effect of anti-cancer medications may not be synergistic, but antagonistic, and should be monitored carefully.

Figure 6. Schematic model of the PDTC suppression effect on luteolin-induced apoptosis in HL-60 cells. PDTC may suppress luteolin-induced apoptosis by inhibiting both the death receptor pathway and the activation of Bad, Bax, and Bcl-XL.

5. Acknowledgements

This work was supported by the grants, NSC98-2320-B- 309-002-MY3 and NSC101-2320-B-309-001 to MingFen Lee and NSC100-2313-B-309-003 to An-Chin Cheng, from National Science Council (Taiwan).

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NOTES

*The authors declare no conflict of interest for this manuscript.

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