Abstract 5431: Histone deacetylase inhibitor (HDAC) panobinostat (LBH589) enhances the antiproliferative effect of a topoisomerase II (topo II) inhibitor in doxorubicin-resistant HL-60 cells, despite high MDR expression

Acute myeloid leukemia (AML) is difficult to treat, particularly in the relapsed or refractory setting due to drug resistance. Topo II inhibitors are effectively used to treat AML, and histone deacetylase (HDAC) inhibitors have been used pre-clinically and clinically with some success. We previously reported that vorinostat (SAHA) was effective in combination with topo II inhibitors in AML cells (Proc. AACR, 2009, Abstract 4567). In the present study we evaluate LBH589, a novel class I/II HDAC inhibitor. Since resistance to HDAC inhibitors has not been well described, we hypothesized that LBH589 would be effective in combination with a topo II inhibitor in a doxorubicin-resistant AML cell line that expresses MDR and resistant by MDR-independent mechanism. A sensitive HL60 parent line (S) and the doxorubicin-resistant sub-line (R) were used. Early studies revealed that vorinostat (SAHA) had comparable anti-proliferative effects in S & R cells but the R cells were relatively more resistant to LBH589. This resistance was likely MDR-mediated. We then tested whether sub-lethal doses of SAHA or LBH589, used in combination with sub-lethal doses of etoposide (VP-16), would be effective. S and R cells were treated with VP-16 for 1 h, washed, and re-incubated with SAHA or LBH, or drug-free media, for a total of 144 hours. Cell viability and apoptosis were measured at 72 h and 144 h following treatment. At 72 h and at 144 h, the combination of VP-16 and LBH was significantly more effective (p Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 5431.