Abstract
Prazosin, a quinazoline-based α1-adrenoceptor antagonist, is known to induce cell death, and this effect is independent of its α-blockade activity. However, the detailed molecular mechanisms involved are still not fully understood. In this study, we found that prazosin, but not doxazosin, could induce patterns of autophagy in H9C2 cells, including intracellular vacuole formation, microtubule-associated protein 1 light chain 3 (LC3) conversion, and acidic vesicular organelle (AVO) augmentation. Western blot analysis of phosphorylated proteins showed that exposure to prazosin increased the levels of phospho-p53 and phospho-adenosine monophosphate-activated protein kinase (AMPK) but dramatically decreased the levels of phospho-mammalian target of rapamycin (mTOR), phospho-protein kinase B (Akt), and phospho-ribosomal protein S6 kinase (p70S6K). Furthermore, although pretreatments with the pharmacological autophagy inhibitor 3-methyladenine and the p53 inhibitor pifithrin-α suppressed prazosin-induced AVO formation, they did not reverse prazosin-induced decline in cell viability but enhanced prazosin-induced caspase-3 activation. From these results we suggest that prazosin induces autophagic cell death via a p53-mediated mechanism. When the autophagy pathway was inhibited, prazosin still induced programmed cell death, at least in part through apoptotic caspase-3 cascade enhancement. Thus, our results indicate a potential new target in prazosin-induced cell death.
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Acknowledgements
The authors thank Wen-Chun Wei and Yao Hsiao for excellent technical assistance. This work was supported by National Science Council, Taiwan [NSC 99-2323-B002-005].
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Yi-Fan Yang and Chau-Chung Wu contributed equally to this work.
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Yang, YF., Wu, CC., Chen, WP. et al. Prazosin induces p53-mediated autophagic cell death in H9C2 cells. Naunyn-Schmiedeberg's Arch Pharmacol 384, 209–216 (2011). https://doi.org/10.1007/s00210-011-0657-3
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DOI: https://doi.org/10.1007/s00210-011-0657-3