Differential response of p53 and p21 on HDAC inhibitor-mediated apoptosis in HCT116 colon cancer cells in vitro and in vivo

  • Authors:
    • Steffen Zopf
    • Daniel Neureiter
    • Steve Bouralexis
    • Tobias Abt
    • Keith B. Glaser
    • Kinya Okamoto
    • Marion Ganslmayer
    • Eckhart G. Hahn
    • Christoph Herold
    • Matthias Ocker
  • View Affiliations

  • Published online on: December 1, 2007     https://doi.org/10.3892/ijo.31.6.1391
  • Pages: 1391-1402
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Abstract

We investigated the effect of a novel histone deacetylase inhibitor, A-423378.0, on the colon carcinoma cell line HCT116 and genetically modified derivatives lacking either p21cip1/waf1 or p53. HCT116 cell lines were incubated with A-423378.0 at different concentrations for 3-120 h. Cell viability, proliferation and apoptosis rates were determined and verified by western blot, detection of mitochondrial membrane potential breakdown ΔΨm, activation of caspases-3, -8 and cytokeratin 18 cleavage. A subcutaneous xenograft model was established in NMRI mice with daily intraperitoneal injections of 10 mg/kg for 14 days. All three HCT116 cell lines responded to A-423378.0 treatment in a dose- and time-dependent manner via induction of apoptosis as measured by breakdown of ΔΨm and BrdU incorporation. We identified that A-423378.0 induced the expression of TRAIL and TRAIL receptor, especially TRAIL-R2/hDR5, which was up-regulated in HCT116 cells after treatment with A-423378.0. In vivo, a growth inhibitory effect was observed with HDAC-I treatment, which was paralleled by a down-regulation of PCNA and a concomitant induction of apoptosis. Treatment of wild-type or knock-out HCT116 cells with A-423378.0 exerts potent anti-proliferative and pro-apoptotic effects in vitro and in vivo. A-423378.0 was able to induce apoptosis in both p21WAF1 and p53 deficient tumour cells, which appeared to be mediated by the intrinsic cell death pathway. Interestingly, the effects of A-423378.0 on the extrinsic cell death pathway through activation of TRAIL and its signalling pathway indicate that A-423378.0 may be a potent new therapeutic compound for the treatment of advanced colorectal cancer.

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December 2007
Volume 31 Issue 6

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

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Spandidos Publications style
Zopf S, Neureiter D, Bouralexis S, Abt T, Glaser KB, Okamoto K, Ganslmayer M, Hahn EG, Herold C, Ocker M, Ocker M, et al: Differential response of p53 and p21 on HDAC inhibitor-mediated apoptosis in HCT116 colon cancer cells in vitro and in vivo. Int J Oncol 31: 1391-1402, 2007
APA
Zopf, S., Neureiter, D., Bouralexis, S., Abt, T., Glaser, K.B., Okamoto, K. ... Ocker, M. (2007). Differential response of p53 and p21 on HDAC inhibitor-mediated apoptosis in HCT116 colon cancer cells in vitro and in vivo. International Journal of Oncology, 31, 1391-1402. https://doi.org/10.3892/ijo.31.6.1391
MLA
Zopf, S., Neureiter, D., Bouralexis, S., Abt, T., Glaser, K. B., Okamoto, K., Ganslmayer, M., Hahn, E. G., Herold, C., Ocker, M."Differential response of p53 and p21 on HDAC inhibitor-mediated apoptosis in HCT116 colon cancer cells in vitro and in vivo". International Journal of Oncology 31.6 (2007): 1391-1402.
Chicago
Zopf, S., Neureiter, D., Bouralexis, S., Abt, T., Glaser, K. B., Okamoto, K., Ganslmayer, M., Hahn, E. G., Herold, C., Ocker, M."Differential response of p53 and p21 on HDAC inhibitor-mediated apoptosis in HCT116 colon cancer cells in vitro and in vivo". International Journal of Oncology 31, no. 6 (2007): 1391-1402. https://doi.org/10.3892/ijo.31.6.1391