Panobinostat (
LBH589) is a highly potent deacetylase inhibitor that has demonstrated clinical efficacy in patients with advanced
cutaneous T-cell lymphoma (CTCL). To gain a better understanding of the compound activity in this
tumor type, we investigated the cellular and molecular effects of
panobinostat using both in vitro and in vivo models of CTCL. All 4 tested CTCL cell lines exhibited very high sensitivity to
panobinostat-induced growth inhibition. However, only 2 of 4 lines exhibited significant response to the cytotoxic activity of
panobinostat. In a CTCL xenograft mouse
tumor model,
panobinostat treatment resulted in complete
tumor regression. The difference in cell sensitivity to
panobinostat-induced death enabled us to further investigate potential mechanisms responsible for
tumor sensitivity or resistance. In CTCL cell lines that were insensitive to
panobinostat-induced apoptosis, constitutively activated
NF-kappaB and high levels of Bcl-2 were observed. Inhibition of Bcl-2 sensitized cells to the cytotoxic activity of
panobinostat. Conversely, knockdown of Bax diminished the CTCL cell sensitivity. Interestingly,
panobinostat could induce cytotoxicity in
vorinostat-resistant CTCL cells by downregulating phosphorylated STAT3 and STAT5
proteins. These studies suggest distinct mechanisms responsible for resistance to different deacetylase inhibitors. We show that the intrinsic apoptotic signaling plays an essential role in mediating
panobinostat anticancer activity. Moreover,
cancer cell sensitivity to
panobinostat treatment may be further improved by combination with inhibition of anti-apoptotic factors. These data provide preclinical support that
panobinostat, as a single agent or in combination with other
anticancer agents, is a promising
therapy for CTCL.