Antileukemia effects of xanthohumol in Bcr/Abl-transformed cells involve nuclear factor-kappaB and p53 modulation.

The oncogenic Bcr-Abl tyrosine kinase activates various signaling pathways including phosphoinositide 3-kinase/Akt and nuclear factor-kappaB that mediate proliferation, transformation, and apoptosis resistance in Bcr-Abl+ myeloid leukemia cells. The hop flavonoid xanthohumol inhibits tumor growth by targeting the nuclear factor-kappaB and Akt pathways and angiogenesis. Here, we show that xanthohumol has in vitro activity against Bcr-Abl+ cells and clinical samples and retained its cytotoxicity when imatinib mesylate-resistant K562 cells were examined. Xanthohumol inhibition of K562 cell viability was associated with induction of apoptosis, increased p21 and p53 expression, and decreased survivin levels. We show that xanthohumol strongly inhibited Bcr-Abl expression at both mRNA and protein levels and show that xanthohumol caused elevation of intracellular reactive oxygen species and that the antioxidant N-acetylcysteine blunted xanthohumol-induced events. Further, we observed that xanthohumol inhibits leukemia cell invasion, metalloprotease production, and adhesion to endothelial cells, potentially preventing in vivo life-threatening complications of leukostasis and tissue infiltration by leukemic cells. As structural mutations and/or gene amplification in Bcr-Abl can circumvent an otherwise potent anticancer drug such as imatinib, targeting Bcr-Abl expression as well as its kinase activity could be a novel additional therapeutic approach for the treatment of Bcr-Abl+ myeloid leukemia.

The transforming growth factor-beta family members bone morphogenetic protein-2 and macrophage inhibitory cytokine-1 as mediators of the antiangiogenic activity of N-(4-hydroxyphenyl)retinamide.

PURPOSE: Tumor growth appears to be an angiogenesis-dependent process. N-(4-hydroxyphenyl)retinamide (fenretinide; 4HPR) has been found to inhibit and/or prevent tumor growth under diverse conditions. Although 4HPR is antiangiogenic, the molecular mechanisms of this effect remain largely unknown. EXPERIMENTAL DESIGN: Endothelial cells were treated with 4HPR in vitro to study the effects on migration, invasion, and organization, as well as gene expression by microarray and quantitative PCR studies. In vivo angiogenesis was evaluated in the Matrigel model. RESULTS: 4HPR treatment substantially modified the biological activities of endothelial cells, repressing their capacity to migrate, invade, and organize into capillary-like structures. The inhibition of invasion induced by 4HPR was also associated with decreased activities of the metalloproteases matrix metalloproteinase-2 and CD13/APN. Using oligonucleotide microarrays, we observed that bone morphogenetic protein-2 and macrophage inhibitory cytokine-1, two multifunctional cytokines of the transforming growth factor-beta family that regulate the growth, differentiation, apoptosis, and matrix accumulation of a variety of cells, are up-regulated in vitro by 4HPR. Both these molecules specifically inhibited endothelial cell growth, migration, and invasion in vitro and suppressed angiogenesis in the Matrigel plug assay in vivo. Blocking antibodies to bone morphogenetic protein-2 were able to reverse the suppressive effects of 4HPR in vitro and in vivo. CONCLUSIONS: These data support the conclusion that 4HPR inhibits tumor growth by repression of new vessel growth and identify novel points of regulation of angiogenesis in transforming growth factor-beta family proteins.

The Akt inhibitor deguelin, is an angiopreventive agent also acting on the NF-kappaB pathway.

Several natural compounds, especially plant products and dietary constituents, are able to exhibit 'angiopreventive' (anti-angiogenic chemoprevention) activities both in vitro and in vivo. Deguelin is a rotenoid of the flavonoid family with chemopreventive activities able to decrease tumor incidence in animal models for lung, colon, mammary and skin carcinogenesis through Akt inhibition. Here we show that deguelin belongs to the 'angiopreventive' molecules and provide evidence for molecular events associated with its anti-angiogenic properties. The data show that deguelin inhibits HUVE cells growth by inducing cell-cycle arrest in the G0/G1 phase and in the absence of apoptosis. Growth arrest is associated with induction of p21 and p53 and decreased survivin levels. Deguelin also interferes with several points in the angiogenic process, including inhibition of endothelial cell migration, invasion and metalloprotease production, and potently inhibits in vivo angiogenesis and vascular tumor growth. In addition to Akt, the nuclear factor-kappaB (NF-kappaB) kinase pathway, which plays a critical role in the regulation of inflammation, vascular homeostasis and angiogenesis, was also repressed by deguelin even in the presence of inflammatory stimuli such as tumor necrosis factor-alpha (TNF-alpha). These findings reveal a new therapeutic potential for deguelin in angioprevention and anti-angiogenic therapy.

AKT/NF-kappaB inhibitor xanthohumol targets cell growth and angiogenesis in hematologic malignancies.

BACKGROUND: Leukemias are dependent on Akt/NF-kappaB activation and angiogenesis. METHODS: The antiangiogenic Akt/NF-kappaB inhibitor xanthohumol (XN) has in vitro activity against acute and chronic myelogenous leukemia cell lines (AML, CML) and fresh samples from patients were investigated. RESULTS: Inhibition of cell proliferation is associated with induction of apoptosis and reduced VEGF secretion. Decreased cell invasion, metalloprotease production, and adhesion to endothelial cells observed in the presence of XN could prevent in vivo life-threatening complications of leukostasis and tissue infiltration. CONCLUSIONS: As endothelial cells and hematopoietic cells are mutually correlated in their development and growth, targeting both tumor cells and endothelial cells with agents possessing cytotoxic and antiangiogenic activities may lead to synergistic antitumor effects interrupting a reciprocal stimulatory loop between leukemia and endothelial cells.