Curcumin-cyclodextrin complexes potentiate gemcitabine effects in an orthotopic mouse model of lung cancer.

BACKGROUND: Overall clinical outcome for advanced lung cancer remains very disappointing despite recent advances in treatment. Curcumin has been reported as potentially active against cancer. METHODS: Owing to poor curcumin solubility, we have used cyclodextrins (CD) as an excipient allowing a considerable increase of aqueous solubility and bioavailability of curcumin. The effects of solubilised curcumin have been evaluated in cell cultures as well as in an in vivo orthotopic lung tumour mouse model. RESULTS: Cell proliferation was reduced while apoptosis rates were increased when lung epithelial tumour cells were cultured in the presence of curcumin-CD complexes. For in vivo experiments, cells were grafted into lungs of C57Bl/6 mice treated by an oral administration of a non-soluble form of curcumin, CDs alone or curcumin-CD complexes, combined or not with gemcitabine. The size of orthotopically implanted lung tumours was reduced upon curcumin complex administration as compared with treatments with placebo or non-solubilised curcumin. Moreover, curcumin potentiated the gemcitabine-mediated antitumour effects. CONCLUSION: Our data demonstrate that curcumin, when given orally in a CD-solubilised form, reduces lung tumour size in vivo. In vitro experiments show impaired tumour cell proliferation and increased cell apoptosis. Moreover, our data underline a potential additive effect of curcumin with gemcitabine thus providing an efficient therapeutic option for antilung cancer therapy.

The metalloproteinase ADAM-12 regulates bronchial epithelial cell proliferation and apoptosis.

OBJECTIVES: The ADAMs (a disintegrin and metalloproteinase) enzymes compose a family of membrane-bound proteins characterized by their multi-domain structure and ADAM-12 expression is elevated in human non-small cell lung cancers. The aim of this study was to investigate the roles played by ADAM-12 in critical steps of bronchial cell transformation during carcinogenesis. MATERIALS AND METHODS: To assess the role of ADAM-12 in tumorigenicity, BEAS-2B cells were transfected with a plasmid encoding human full-length ADAM-12 cDNA, and then the effects of ADAM-12 overexpression on cell behaviour were explored. Treatment of clones with heparin-binding epidermal growth factor (EGF)-like growth factor (HB-EGF) neutralizing antibodies as well as an EGFR inhibitor allowed the dissection of mechanisms regulating cell proliferation and apoptosis. RESULTS: Overexpression of ADAM-12 in BEAS-2B cells promoted cell proliferation. ADAM-12 overexpressing clones produced higher quantities of HB-EGF in their culture medium which may rely on membrane-bound HB-EGF shedding by ADAM-12. Targeting HB-EGF activity with a neutralizing antibody abrogated enhanced cell proliferation in the ADAM-12 overexpressing clones. In sharp contrast, targeting of amphiregulin, EGF or transforming growth factor-alpha failed to influence cell proliferation; moreover, ADAM-12 transfectants were resistant to etoposide-induced apoptosis and the use of a neutralizing antibody against HB-EGF activity restored rates of apoptosis to be similar to controls. CONCLUSIONS: ADAM-12 contributes to enhancing HB-EGF shedding from plasma membranes leading to increased cell proliferation and reduced apoptosis in this bronchial epithelial cell line.

Emerging roles of ADAM and ADAMTS metalloproteinases in cancer.

A disintegrin and metalloproteinases (ADAMs) are a recently discovered family of proteins that share the metalloproteinase domain with matrix metalloproteinases (MMPs). Among this family, structural features distinguish the membrane-anchored ADAMs and the secreted ADAMs with thrombospondin motifs referred to as ADAMTSs. By acting on a large panel of membrane-associated and extracellular substrates, they control several cell functions such as adhesion, fusion, migration and proliferation. The current review addresses the contribution of these proteinases in the positive and negative regulation of cancer progression as mainly mediated by the regulation of growth factor activities and integrin functions.

Expression of a disintegrin and metalloprotease (ADAM and ADAMTS) enzymes in human non-small-cell lung carcinomas (NSCLC).

A Disintegrin and Metalloprotease (ADAM) are transmembrane proteases displaying multiple functions. ADAM with ThromboSpondin-like motifs (ADAMTS) are secreted proteases characterised by thrombospondin (TS) motifs in their C-terminal domain. The aim of this work was to evaluate the expression pattern of ADAMs and ADAMTS in non small cell lung carcinomas (NSCLC) and to investigate the possible correlation between their expression and cancer progression. Reverse transcriptase-polymerase chain reaction (RT-PCR), Western blot and immunohistochemical analyses were performed on NSCLC samples and corresponding nondiseased tissue fragments. Among the ADAMs evaluated (ADAM-8, -9, -10, -12, -15, -17, ADAMTS-1, TS-2 and TS-12), a modulation of ADAM-12 and ADAMTS-1 mRNA expression was observed. Amounts of ADAM-12 mRNA transcripts were increased in tumour tissues as compared to the corresponding controls. In sharp contrast, ADAMTS-1 mRNA levels were significantly lower in tumour tissues when compared to corresponding nondiseased lung. These results were corroborated at the protein level by Western blot and immunohistochemistry. A positive correlation was observed between the mRNA levels of ADAM-12 and those of two vascular endothelial growth factor (VEGF)-A isoforms (VEGF-A(165) and VEGF-A(121)). Taken together, these results providing evidence for an overexpression of ADAM-12 and a lower expression of ADAMTS-1 in non-small-cell lung cancer suggest that these proteases play different functions in cancer progression.

[Determination of plasma concentrations of antioxidants, antibodies against oxidized LDL, and homocysteine in a population sample from Liège]. / Evaluation des concentrations plasmatiques en anti-oxydants, anticorps contre les LDL oxydées et homocystéine dans un echantillon de la population liégeoise.

A large number of epidemiological and clinical studies suggest that oxidative stress plays an important role in the development of cardiovascular diseases. In this way, following reference values in plasmatic antioxidants have been determined in a group of 123 blood donors (94 males, 29 females; age: 21-64 years) living in the surroundings of Liege, Belgium: vitamin A (1.5-3.62 mmol/l), vitamin C (3.68-75.21 mmol/l), vitamin E (16.98-46.46 mmol/l), ratio vitamin E/cholesterol (3.92-8.32 mmol/mmol), selenium (0.66-1.26 mmol/l), sulphydryl proteins (216-556 mmol/l), uric acid (174-477 mmol/l), superoxide dismutase (542-852 IU/g hemoglobine), glutathion peroxidase (39.55-91.83 IU/g hemoglobine). Only a few number of subjects were found with values corresponding to high risk of deficiency in antioxidants although low values in vitamin C (< 11.35 mmol/l) and in selenium (< 0.75 mmol/l) were respectively observed in 5.69 and 10.5% of our subjects. Autoantibodies against oxidized LDL, as marker of oxidative stress, and homocysteine, as a risk factor of atherosclerosis involved in the development of oxidative stress, have also been investigated. Approximatively 40% of the population presented values higher than the superior limit mean value (20.3% > 650 IU/l in autoantibodies and 19.5% > 15.2 mmol/l in homocysteine) that are, however, not correlated with age or low levels in antioxidants. The effect of smoking (25% of the population) contributed to significantly decrease vitamin C, selenium and glutathion peroxidase concentrations by 31.9 and 13% when compared to nonsmokers. Intake of 1 to 4 fruits per day resulted in a significant increase of 56.9% in vitamin C when compared to nonconsumers (26.8% of the population). In contrast, homocysteine concentrations were significantly decreased by 21.4% in fruits consumers. Thank to the development of methods allowing the routine dosage of all these parameters, general practitioners can now easily establish the oxidative stress status of their patients and, as fonction of getting patterns, detect populations at risk of developing cardiovascular diseases.

Trace metal content of cerebral vessels in American Blacks, Caucasians and Nigerian Africans.

Trace metal contents of cerebral vessels in age-matched and sex-matched subjects from three population groups were estimated. The trace metals included calcium, manganese, zinc, magnesium, copper and iron. The American blacks in Washington, D.C., who are ethnologically related to Nigerian Africans, have different patterns of trace metal contents in their cerebral vessels and the observed levels also differed in some respects from Minnesota Caucasians living in a similar environment. The greatest amounts of calcium, zinc, and copper were found in the vessels of American blacks while the greatest amount of magnesium was found in vessels of Minnesota Caucasians. There was no statistically significant difference in the manganese content of the cerebral vessels in three population groups. Nigerian Africans had the least amounts of copper and magnesium but had the highest iron content. A similar high level of iron was observed in the vessels of American blacks. Since it has been shown that American blacks have the most extensive and severe degree of atherosclerosis among the three population groups, it would appear that iron, calcium and manganese in the cerebral vessels may not directly relate to the severity of cerebral atherosclerosis. Relatively high levels of copper and magnesium, which were observed in the cerebral vessels of American blacks and Caucasians, may be of significance in the pathogenesis of cerebral atherosclerosis. The low levels of the trace metals in Nigerians may be protective. The possible role of zinc requires further studies.