bergamottin and Leukemia--Myelogenous--Chronic--BCR-ABL-Positive

Context Simvastatin (SV) and bergamottin (BGM) are known to exhibit diverse anti-cancer and anti-inflammatory activities. Objective Very little is known about the potential efficacy of combination of these two agents to potentiate TNF-induced apoptosis in human chronic myelogenous leukaemia (CML). Materials and methods In the present study, we investigated whether SV combined with BGM mediates its effect through suppression of NF-κB-signalling pathway. Results We found that the combination treatment enhanced cytotoxicity and potentiated the apoptosis induced by TNF as indicated by intracellular esterase activity, Annexin V staining and caspase activation. This effect of co-treatment correlated with down-regulation of various gene products that mediate cell proliferation (cyclin D1), cell survival (cIAP-1, Bcl-2, Bcl-xL and Survivin), invasion (MMP-9) and angiogenesis (VEGF); all known to be regulated by NF-κB. SV combined with BGM also produced TNF-induced cell-cycle arrest in S-phase and this arrest correlated with a concomitant increase in the levels of cyclin-dependent inhibitor p21 and p27. The combination therapy inhibited TNF-induced NF-κB activation, IκBα degradation and p65 translocation to the nucleus as compared with the treatment with individual agents alone. Besides, SV combined with BGM did not significantly potentiate apoptotic effect induced by TNF in p65(-)(/)(-) cells, as compared with wild-type fibroblasts. Discussion and conclusion Our results provide novel insight into the role of SV and BGM in potentially preventing and treating cancer through modulation of NF-κB signalling pathway and its regulated gene products.

Topics: Active Transport, Cell Nucleus; Animals; Antineoplastic Combined Chemotherapy Protocols; Apoptosis; Apoptosis Regulatory Proteins; Cell Cycle Proteins; Cell Line, Tumor; Dose-Response Relationship, Drug; Drug Synergism; Furocoumarins; Gene Expression Regulation, Neoplastic; Humans; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Matrix Metalloproteinase 9; Mice; NF-kappa B; NF-KappaB Inhibitor alpha; Proteolysis; S Phase Cell Cycle Checkpoints; Signal Transduction; Simvastatin; Time Factors; Transcription Factor RelA; Tumor Necrosis Factor-alpha; Vascular Endothelial Growth Factor A

We investigated the effects of the ethyl acetate extract of grapefruit juice (GFJ), that of orange juice (OJ) and their components on the uptake of [(3)H]vincristine into adriamycin-resistant human myelogenous leukemia cells. Its uptake was increased by the extracts of GFJ and OJ up to 7- and 3-fold, respectively, as well as verapamil and cyclosporin A. OJ components, i.e. 3,3',4',5,6,7,8-heptamethoxyflavone, nobiletin and tangeretin, also increased the uptake of [(3)H]vincristine in a concentration-dependent manner. Although GFJ components, dihydroxybergamottin and bergamottin, significantly increased the uptake, their potencies were considerably weaker than those of OJ components. These data suggest that OJ components inhibit P-gp-mediated efflux of [(3)H]vincristine, resulting in the intracellular accumulation of chemotherapeutic drugs. These components may become candidates of multi-drug resistance reversing agents in cancer chemotherapy.

Topics: Acetates; ATP Binding Cassette Transporter, Subfamily B; Beverages; Blotting, Western; Citrus; Cyclosporine; Dose-Response Relationship, Drug; Doxorubicin; Drug Resistance, Multiple; Drug Resistance, Neoplasm; Flavones; Flavonoids; Furocoumarins; Humans; K562 Cells; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Plant Extracts; Tritium; Verapamil; Vincristine