Abstract

Abstract Background. Liver cancer still represents an unmet medical need with rising incidence rates also in Western countries. Panobinostat (LBH589, Novartis Oncology), a pandeacetylase inhibitor, represents a new agent with a promising future in liver cancer therapy. We have previously demonstrated that panobinostat is able to induce cell death in two liver cancer cell lines, HepG2 and Hep3B, through activation of ER stress related apoptotic pathways (Cell Oncol 2010;32:285-300). Panobinostat also significantly reduced the growth of HepG2 xenografts in nu/nu mice. We here demonstrate the implication of autophagy mechanisms into cell demise mediated by panobinostat. Materials and Methods. HepG2 (p53 wt) and Hep3B (p53 null) were treated for 72 hours with panobinostat and cell death was quantified through FACS with propidium ioded staining and CK18 fragmentation staining. Impedance based real-time cell analysis was performed to continuously monitor cell viability after panobinostat treatment. The expression of autophagy related factors was analyzed through RT-qPCR, western blot and immunofluorescence based cytochemistry. Results. Panobinostat induces cell death in a dose and time dependent manner. Autophagy related factors Atg5, Beclin and its activators Ambra, p62 and UVRAG were up-regulated after 48 hours of treatment. We also observed also significant increase of p73 expression in Hep3B cells after 24 hours of treatment. Immunofluorescence based cytochemistry showed a modification of the ubiquitous cytosolic distribution of Beclin and LC3B in both cell lines to a defined spot formation after treatment with panobinostat, indicating a probable autophagosome formation. Western blot analysis also demonstrated an increase of Beclin and LC3-I and LC3-II. Conclusion. Panobinostat treatment determines the involvement of autophagy related mechanisms in a ER stress related apoptosis scenario. The wide spectrum of mechanisms of action of panobinostat need to be further investigated. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 2873. doi:10.1158/1538-7445.AM2011-2873

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