xanthohumol and Cell-Transformation--Neoplastic

Despite recent advances in understanding the biological basis of prostate cancer, management of the disease, especially in the phase resistant to androgen ablation, remains a significant challenge. The long latency and high incidence of prostate carcinogenesis provides the opportunity to intervene with chemoprevention to prevent or eradicate prostate malignancies. In this study, we have used human hormone-resistant prostate cancer cells, DU145 and PC3, as an in vitro model to assess the efficacy of xanthohumol (XN) against cell growth, motility and invasion. We observed that treatment of prostate cancer cells with low micromolar doses of XN inhibits proliferation and modulates focal adhesion kinase (FAK) and AKT phosphorylation leading to reduced cell migration and invasion. Oxidative stress by increased production of reactive oxygen species (ROS) was associated with these effects. Transgenic adenocarcinoma of the mouse prostate (TRAMP) transgenic mice were used as an in vivo model of prostate adenocarcinoma. Oral gavage of XN, three times per week, beginning at 4 wks of age, induced a decrease in the average weight of the urogenital (UG) tract, delayed advanced tumor progression and inhibited the growth of poorly differentiated prostate carcinoma. The ability of XN to inhibit prostate cancer in vitro and in vivo suggests that XN may be a novel agent for the management of prostate cancer.

Topics: Administration, Oral; Androgens; Animals; Antineoplastic Agents; Cell Line, Tumor; Cell Movement; Cell Proliferation; Cell Transformation, Neoplastic; Disease Progression; Dose-Response Relationship, Drug; Drug Screening Assays, Antitumor; Flavonoids; G1 Phase; Humans; Male; Mice; Mice, Inbred C57BL; Mice, Transgenic; Neoplasm Invasiveness; Neoplasm Staging; Propiophenones; Prostatic Neoplasms; Reactive Oxygen Species; Resting Phase, Cell Cycle

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.

Topics: Antineoplastic Agents; Apoptosis; Benzamides; Cell Adhesion; Cell Proliferation; Cell Survival; Cell Transformation, Neoplastic; Down-Regulation; Drug Resistance, Neoplasm; Drug Screening Assays, Antitumor; Endothelial Cells; Extracellular Matrix; Flavonoids; Fusion Proteins, bcr-abl; Gene Expression Regulation, Leukemic; Humans; Imatinib Mesylate; K562 Cells; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Neoplasm Invasiveness; Neovascularization, Pathologic; NF-kappa B; Piperazines; Propiophenones; Pyrimidines; Reactive Oxygen Species; Tumor Suppressor Protein p53; U937 Cells; Vascular Endothelial Growth Factor A