Abstract 3650: In Vitro and in vivo synergistic anticancer effect of HDAC inhibitor panobinostat (LBH589) plus zoledronic acid in human prostate, breast and multiple myeloma tumor models

Abstract

Abstract Prostate cancer (PCa), multiple myeloma (MM) as well as triple-negative breast cancers (TNBCa) (lacking ER, PR, and ErbB2 receptor) are associated with aggressive behaviour, poor prognosis, and limited response to conventional chemotherapy as well as to molecular targeted drugs, in advanced disease. On this regards, the recent availability of agents able to regulate many signaling pathways, such as HDAC inhibitors (HDAC-Is) as well as bisphosphonates (BPs), can help to overcome the existence limited activity of anticancer strategies. The HDAC-I Panobinostat (LBH589) has shown significant preclinical and clinical anticancer activity in both haematological and solid malignancies, and is currently in phase III for relapsed MM. BPs, such as zoledronic acid (ZOL), inhibit osteoclast-mediated bone resorption and are indicated for the treatment of cancer bone metastasis. In addition a direct and indirect anticancer activity of ZOL in several preclinical models and clinical studies have been observed. In our study, we sought to define preclinically, the potential anticancer effect of Panobinostat in combination with ZOL in several cell models. We showed a potent synergistic antiproliferative effect of Panobinostat/ZOL treatment in PC3, LNCAP and DU145 PCa cells, independently of p53/KRAS status as well as androgen dependency, whatever schedule of administration (simultaneous vs sequential) we used, as demonstrated by median drug effect analysis calculating combination index (CI) according to the method of Chou and Talalay (CI<1). Similar results were obtained in MM cells (RPMI and U266 and LP1, KMS12BM, KMS21BM). Moreover, consistent preliminary results showed sequence-dependent synergistic/additive effect in TNBCa cells. We also demonstrated that the combination of Panobinostat and ZOL, compared to single agents treatment, increased apoptotic cell death as demonstrated by Annexin V-FITC staining, and PARP cleavage, in both PCa and MM cells. The oxidative injury may play a functional role in the observed increase cell death, because co-administration of the antioxidant N-acetyl-L-cystein blocked reactive oxygen species generation and apoptosis. Furthermore, a synergistic inhibition of cancer cell migration and invasion in the combination setting compared to single drug treatment were observed. At the molecular level the observed anticancer synergistic effect could be, at least in part, related to the ability of Panobinostat to downregulate the activation of p38MAPK induced by ZOL, which has been described as a mechanism of resistance to aminoBPs treatment. The synergistic anticancer effect of Panobinostat/ZOL combination was confirmed in vivo in PCa DU145 cells xenograft model, where we observed a marked inhibition of tumor growth in the combination-treated group compared to controls and single agents treated group. 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 3650.