Lan Li1, Fadi S Braiteh, Razelle Kurzrock. 1. Division of Cancer Medicine, Phase I Program and Department of Gastrointestinal Medical Oncology, The University of Texas M. D. Anderson Cancer Center, Houston, 77230, USA.
Abstract
BACKGROUND: Because a role for nuclear factor-kappaB (NF-kappaB) has been implicated in the pathogenesis of pancreatic carcinoma, this transcription factor is a potential target for the treatment of this devastating disease. Curcumin (diferuloylmethane) is a phytochemical with potent NF-kappaB-inhibitory activity. It is pharmacologically safe, but its bioavailability is poor after oral administration. METHODS: The authors encapsulated curcumin in a liposomal delivery system that would allow intravenous administration. They studied the in vitro and in vivo effects of this compound on proliferation, apoptosis, signaling, and angiogenesis using human pancreatic carcinoma cells. NF-kappaB was constitutively active in all human pancreatic carcinoma cell lines evaluated and liposomal curcumin consistently suppressed NF-kappaB binding (electrophoretic mobility gel shift assay) and decreased the expression of NF-kappaB-regulated gene products, including cyclooxygenase-2 (immunoblots) and interleukin-8 (enzyme-linked immunoassay), both of which have been implicated in tumor growth/invasiveness. These in vitro changes were associated with concentration and time-dependent antiproliferative activity (3-[4,5-dimethylthiazol-2-yl]2,5-diphenyltetrazolium bromide assay [MTT assay]) and proapoptotic effects (annexin V/propidium iodide staining [fluorescence-activated cell sorting] and polyadenosine-5'-diphosphate-ribose-polymerase cleavage). RESULTS: The activity of liposomal curcumin was equal to or better than that of free curcumin at equimolar concentrations. In vivo, curcumin suppressed pancreatic carcinoma growth in murine xenograft models and inhibited tumor angiogenesis. CONCLUSIONS: Liposomal curcumin down-regulated the NF-kappaB machinery, suppressed growth, and induced apoptosis of human pancreatic cells in vitro. Antitumor and antiangiogenesis effects were observed in vivo. The experiments in the current study provide a biologic rationale for treatment of patients suffering from pancreatic carcinoma with this nontoxic phytochemical encapsulated in liposomes for systemic delivery. Copyright 2005 American Cancer Society.
BACKGROUND: Because a role for nuclear factor-kappaB (NF-kappaB) has been implicated in the pathogenesis of pancreatic carcinoma, this transcription factor is a potential target for the treatment of this devastating disease. Curcumin (diferuloylmethane) is a phytochemical with potent NF-kappaB-inhibitory activity. It is pharmacologically safe, but its bioavailability is poor after oral administration. METHODS: The authors encapsulated curcumin in a liposomal delivery system that would allow intravenous administration. They studied the in vitro and in vivo effects of this compound on proliferation, apoptosis, signaling, and angiogenesis using humanpancreatic carcinoma cells. NF-kappaB was constitutively active in all humanpancreatic carcinoma cell lines evaluated and liposomal curcumin consistently suppressed NF-kappaB binding (electrophoretic mobility gel shift assay) and decreased the expression of NF-kappaB-regulated gene products, including cyclooxygenase-2 (immunoblots) and interleukin-8 (enzyme-linked immunoassay), both of which have been implicated in tumor growth/invasiveness. These in vitro changes were associated with concentration and time-dependent antiproliferative activity (3-[4,5-dimethylthiazol-2-yl]2,5-diphenyltetrazolium bromide assay [MTT assay]) and proapoptotic effects (annexin V/propidium iodide staining [fluorescence-activated cell sorting] and polyadenosine-5'-diphosphate-ribose-polymerase cleavage). RESULTS: The activity of liposomal curcumin was equal to or better than that of free curcumin at equimolar concentrations. In vivo, curcumin suppressed pancreatic carcinoma growth in murine xenograft models and inhibited tumor angiogenesis. CONCLUSIONS: Liposomal curcumin down-regulated the NF-kappaB machinery, suppressed growth, and induced apoptosis of human pancreatic cells in vitro. Antitumor and antiangiogenesis effects were observed in vivo. The experiments in the current study provide a biologic rationale for treatment of patients suffering from pancreatic carcinoma with this nontoxic phytochemical encapsulated in liposomes for systemic delivery. Copyright 2005 American Cancer Society.