Sirtinol, a class III HDAC inhibitor, induces apoptotic and autophagic cell death in MCF-7 human breast cancer cells

  • Authors:
    • Jing Wang
    • Tae Hyung Kim
    • Mee Young Ahn
    • Jaewon Lee
    • Jee H. Jung
    • Wahn Soo Choi
    • Byung Mu Lee
    • Kyuing Sil Yoon
    • Sungpil Yoon
    • Hyung Sik Kim
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  • Published online on: June 26, 2012     https://doi.org/10.3892/ijo.2012.1534
  • Pages: 1101-1109
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Abstract

Sirtuins (SIRTs), NAD+-dependent class III histone deacetylases (HDACs), play an important role in the regulation of cell division, survival and senescence. Although a number of effective SIRT inhibitors have been developed, little is known about the specific mechanisms of their anticancer activity. In this study, we investigated the anticancer effects of sirtinol, a SIRT inhibitor, on MCF-7 human breast cancer cells. Apoptotic and autophagic cell death were measured. Sirtinol significantly inhibited the proliferation of MCF-7 cells in a concentration-dependent manner. The IC50 values of sirtinol were 48.6 µM (24 h) and 43.5 µM (48 h) in MCF-7 cells. As expected, sirtinol significantly increased the acetylation of p53, which has been reported to be a target of SIRT1/2. Flow cyto­metry analysis revealed that sirtinol significantly increased the G1 phase of the cell cycle. The upregulation of Bax, downregulation of Bcl-2 and cytochrome c release into the cytoplasm, which are considered as mechanisms of apoptotic cell death, were observed in the MCF-7 cells treated with sirtinol. The annexin V-FITC assay was used to confirm sirtinol-induced apoptotic cell death. Furthermore, the expression of LC3-II, an autophagy-related molecule, was significantly increased in MCF-7 cells after sirtinol treatment. Autophagic cell death was confirmed by acridine orange and monodansylcadaverine (MDC) staining. Of note, pre-treatment with 3-methyladenine (3-MA) increased the sirtinol-induced MCF-7 cell cytotoxicity, which is associated with blocking autophagic cell death and increasing apoptotic cell death. Based on our results, the downregulation of SIRT1/2 expression may play an important role in the regulation of breast cancer cell death; thus, SIRT1/2 may be a novel molecular target for cancer therapy and these findings may provide a molecular basis for targeting SIRT1/2 in future cancer therapy.
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September 2012
Volume 41 Issue 3

Print ISSN: 1019-6439
Online ISSN:1791-2423

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Spandidos Publications style
Wang J, Kim TH, Ahn MY, Lee J, Jung JH, Choi WS, Lee BM, Yoon KS, Yoon S, Kim HS, Kim HS, et al: Sirtinol, a class III HDAC inhibitor, induces apoptotic and autophagic cell death in MCF-7 human breast cancer cells. Int J Oncol 41: 1101-1109, 2012.
APA
Wang, J., Kim, T.H., Ahn, M.Y., Lee, J., Jung, J.H., Choi, W.S. ... Kim, H.S. (2012). Sirtinol, a class III HDAC inhibitor, induces apoptotic and autophagic cell death in MCF-7 human breast cancer cells. International Journal of Oncology, 41, 1101-1109. https://doi.org/10.3892/ijo.2012.1534
MLA
Wang, J., Kim, T. H., Ahn, M. Y., Lee, J., Jung, J. H., Choi, W. S., Lee, B. M., Yoon, K. S., Yoon, S., Kim, H. S."Sirtinol, a class III HDAC inhibitor, induces apoptotic and autophagic cell death in MCF-7 human breast cancer cells". International Journal of Oncology 41.3 (2012): 1101-1109.
Chicago
Wang, J., Kim, T. H., Ahn, M. Y., Lee, J., Jung, J. H., Choi, W. S., Lee, B. M., Yoon, K. S., Yoon, S., Kim, H. S."Sirtinol, a class III HDAC inhibitor, induces apoptotic and autophagic cell death in MCF-7 human breast cancer cells". International Journal of Oncology 41, no. 3 (2012): 1101-1109. https://doi.org/10.3892/ijo.2012.1534