Poster Presentation 25th Lorne Cancer Conference 2013

Continuous Treatment With Low Concentrations of the Histone Deacetylase Inhibitor LBH589 Induces Terminal Differentiation of Osteosarcoma Cells (#129)

Jason Cain 1 , Andrew McCaw 1 , Samantha Jayasekara 1 , Fernando Rossello 1 , Kieren Marini 1 , Aaron Irving 1 , Maya Kansara 2 , David Thomas 2 , David Ashley 1 3 , Neil Watkins 1
  1. MIMR, Monash University, Clayton, Vic, Australia
  2. Peter MacCallum Cancer Centre, East Melbourne, Vic, Australia
  3. Deakin University / Barwon Health, Geelong, Vic, Australia
Histone deacetylase inhibitors (HDACi) were identified nearly four decades ago based on their ability to induce cellular differentiation. However, the preclinical and clinical development of these compounds as cancer therapies has focused almost entirely on their capacity to induce apoptosis in hematologic and lymphoid malignancies, often in combination with conventional cytotoxic agents. In many cases, the doses of HDACi necessary to induce these effects result in significant toxicity. Prompted by the capacity of osteosarcoma cells to express markers of terminal osteoblast differentiation in response to DNA methyltransferase inhibitors, we hypothesized that the epigenetic reprogramming capacity of HDACi might be exploited for therapeutic benefit. Here, we show that continuous exposure of osteosarcoma cells to low concentrations of HDACi LBH589 (Panobinostat) induces terminal osteoblast differentiation and irreversible senescence over a three-week period without inducing cell death. Remarkably, transcriptional profiling revealed that HDACi therapy initiated gene signatures characteristic of chondrocyte and adipocyte lineages in addition to marked upregulation of mature osteoblast markers. Although histone and tubulin acetylation was readily detectable in response to HDACi treatment, we did not observe acetylation of p53, indicating that cell senescence is due to p53-independent mechanism. In a mouse xenograft model, continuous low dose treatment with LBH589 induced a sustained cytostatic response accompanied by marked induction of mature osteoblast gene expression. These data suggest that the remarkable capacity of osteosarcoma cells to differentiate in response to HDACi therapy could be exploited for therapeutic benefit without inducing cell death or systemic toxicity.