Abstract B202: A new curcumin analogue compound endowed with strong antitumor activity against neuroectoderma-derived cancers

Abstract

Abstract Sharing the common neuroectodermal origin, Malignant Melanoma (MM) and Neuroblastoma (NB) are tumors widely diffused among adult and children, respectively. Despite the current advances in treatment options, clinical prognosis of aggressive neuroectodermal cancers remains dismal. Chemotherapeutics currently in use are still unsatisfactory, therefore the search for novel therapies for such tumors is warranted. Curcumin, main component of curry spice, is one of the phytochemicals widely studied for its antioxidant, anti-inflammatory and anti-cancer properties. Moreover, it has been reported that curcumin exerts a good anti-proliferative activity on neuroectodermal tumor cells by inducing apoptosis. Recently, we have synthetized and tested in vitro various curcumin related compounds in order to select new antitumor agents displaying stronger and selective growth inhibition activity on both MM and NB cells. In this work, we have demonstrated that a new curcumin-related biphenyl compound, the α,β unsaturated keton (D6), was more effective in inhibiting tumor cells growth when compared to curcumin (D6 IC50 ∼1-2µM, vs curcumin IC50 ∼10-20µM). Normal fibroblasts proliferation was not affected by these treatments. Clonogenic assay, which measures the long-term effects of drugs on permanent cell growth arrest and cell death, showed a significant dose-dependent reduction in both MM and NB colony formation only after D6 treatment. Furthermore, TUNEL assay, Annexin V staining, caspases activation (such as caspases 3, 7, 9) and PARP cleavage unveiled the ability of D6 to cause tumor cell death by triggering apoptosis, similarly to curcumin, but with a stronger and quicker extent. Besides, these apoptotic features appear to be associated with loss of mitochondrial membrane potential and cytochrome c release, meaning that also the intrinsic apoptotic route took place. As reported in literature, curcumin inhibited NFkB nuclear translocation in neuroectodermal tumor cells and, therefore, D6 showed the same inhibitory effects but at lower doses. In vivo anti-tumor activity of curcumin and D6 was surveyed using sub-cutaneous MM and orthotopic NB xenograft models. In both experiments, D6 exibited significantly reduced tumor growth compared to both control and curcumin (MM: D6 vs control: P<0.001 and D6 vs curcumin P<0.01; NB: D6 vs both control and curcumin: P<0.001). Our data indicate the biphenyl curcumin-related compound D6 could be considered as a good candidate to develop new adjuvant therapies against tumors with neuroectodermal origin. Citation Information: Mol Cancer Ther 2009;8(12 Suppl):B202.