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At least 1,009 records · Page 56Linked to original sources
PubMed2002

Multiple actions of the chemokine CXCL12 on epithelial tumor cells in human ovarian cancer.

Of 14 chemokine receptors investigated, only CXCR4 was expressed on ovarian cancer cells [C. J. Scotton et al., Cancer Res., 61: 4961-4965, 2001]. To further understand the role of this chemokine receptor in ovarian tumor biology, we studied the action of its ligand, CXCL12 (stromal cell-derived factor 1), on the CXCR4-expressing ovarian cancer cell lines IGROV. Ligand stimulation of the CXCR4 receptor resulted in sustained activation of Akt/protein kinase B and biphasic phosphorylation of p44/42 mitogen-activated protein kinase in IGROV. When IGROV cells were cultured under suboptimal conditions, CXCL12 stimulated their in vitro growth, an effect that was abrogated by neutralizing antibodies to CXCR4. This increase in cell number was attributable to stimulation of DNA synthesis, not protection from apoptosis. CXCL12 treatment of IGROV cells also induced mRNA and protein for tumor necrosis factor alpha, a cytokine that is expressed by tumor cells in ovarian cancer biopsies. IGROV cells invaded through Matrigel toward a CXCL12 gradient. Invasion was abrogated by the broad spectrum matrix metalloproteinase and TNFalpha converting enzyme inhibitor Marimastat and was partially inhibited by neutralizing antitumor necrosis factor alpha antibodies. These effects were not limited to the IGROV cell line. They could also be demonstrated in the CAOV-3 ovarian cancer cell line and primary ovarian tumor cells isolated from ovarian ascites. These biological effects of CXCL12 on IGROV cells were also inhibited by the small molecular weight CXCR4 antagonist AMD3100. Finally, we found abundant intracellular CXCL12 protein in tumor cells in 15 of 18 ovarian cancer biopsies but not in epithelial cells from normal ovary or borderline disease. The chemokine CXCL12 may have multiple biological effects in ovarian cancer, stimulating cell migration and invasion through extracellular matrix, as well as DNA synthesis and establishment of a cytokine network in situations that are suboptimal for tumor cell growth.

Benzylamines↗
PubMed2003

Reduced fitness of HIV-1 resistant to CXCR4 antagonists.

HIV-1 strains with a syncytium-inducing phenotype that use CXCR4 (X4 strains) have been associated with faster disease progression and AIDS. Antiviral agents designed to block CXCR4 may prevent the emergence of X4 HIV strains but resistant strains that maintain the X4 phenotype can be raised by sequential passage in cell cultures. We have demonstrated that a laboratory adapted strain (NL4-3) and a cloned clinical isolate (CI-1) of HIV-1 cultured in the presence of the CXCR4 antagonist, AMD3100, became resistant to the compound without a change in co-receptor use. These strains became resistant through divergence with respect to the wild-type virus. Conversely, a clinical isolate made resistant to AMD3100 switched co-receptor use from X4 to R5 through a change in diversity from the original virus population. When dual infection competition/heteroduplex tracking assays were performed, all AMD3100-resistant strains, regardless of co-receptor use showed a significantly diminished fitness compared with the wild-type virus. Single virus infections, at a similar multiplicity of infection, also indicated that the wild-type strains possess better replicative ability than their corresponding resistant strains. Thus, viral resistance development to a CXCR4 antagonist such as AMD3100 is associated with reduced viral fitness.

Amino Acid Sequence↗
PubMed2003

Brain-derived neurotrophic factor inhibits human immunodeficiency virus-1/gp120-mediated cerebellar granule cell death by preventing gp120 internalization.

The human immunodeficiency virus type 1 (HIV-1) envelope protein gp120 has been implicated in the pathogenesis of HIV-1 dementia. Thus, inhibition of gp120 activity could reduce HIV toxicity in the brain. We have used primary cultures of rat cerebellar granule cells to examine mechanisms whereby gp120 causes cell death and to characterize neuroprotective agents. gp120 induced a time- and concentration-dependent apoptotic cell death, which was caspase-3-mediated but caspase-1 independent, and was totally blocked by the irreversible caspase-3-like protease inhibitor N-acetyl-Asp-Glu-Val-Asp-chloromethylketone. Caspase-3 activation was observed only in neurons that internalize gp120, indicating that internalization is key to gp120 toxicity. Because brain-derived neurotrophic factor (BDNF) prevents caspase-3-mediated neuronal cell death, we examined whether BDNF could prevent gp120-mediated apoptosis. Preincubation of neurons with BDNF before the addition of gp120 reduced caspase-3 activation, and consequently rescued 80% of neurons from apoptosis. Most importantly, BDNF reduced the levels of CXC chemokine receptor-4 (CXCR4), a receptor that mediates HIV-1 gp120-induced apoptosis. This effect correlated with the ability of BDNF to reduce gp120 internalization and apoptosis. Moreover, BDNF blocked the neurotoxic effect of stromal-derived factor-1alpha, a natural ligand for CXCR4, further establishing a correlation between neuroprotection and downregulation of CXCR4. We propose that BDNF may be a valid therapy to slow down the progression of HIV/gp120-mediated neurotoxicity.

Animals↗
PubMed2003

X4 HIV-1 induces neuroblastoma cell death by interference with CXCL12/CXCR4 interaction.

Human neuroblastoma SK-N-SH cells strongly express CXC-chemokine receptor 4 (CXCR4), the principal coreceptor for X4 HIV-1 strains, and its natural ligand stromal cell-derived factor 1 (SDF-1, recently renamed CXCL12). We investigated the impact of CXCR4 blockade by the specific CXCR4 antagonist AMD3100 or by X4 HIV-1 virus particles on the growth and survival of neuroblastoma SK-N-SH cells. SK-N-SH cell proliferation was inhibited byAMD3100 and anti-CXCL12 neutralizing antibodies, but enhanced by exogenously added CXCL12. Upon prolongedexposure to AMD3100, SK-N-SH cell death occurred throughdeficit of survival-promoting and growth-stimulatory signals generated by endogenous CXCL12. In analogy with the observations made with the CXCR4 inhibitor AMD3100, the X4 HIV-1 strains IIIB and SF-2, but not the R5 strain BaL, caused a marked cytopathic effect and strongly effected SK-N-SH cell death after at least 10 days of incubation. However, no virus production could be detected in the HIV-1-inoculated SK-N-SH cell cultures. Exogenously added CXCL12 afforded partial protection against X4 HIV-1-induced cytopathicity in SK-N-SH cells. Our data indicate that the endogenous CXCL12/CXCR4 signaling axis is critical for neuroblastoma cell survival and proliferation. Long-term blockade of CXCR4 through physical contact with the X4 HIV-1 envelope can cause neuronal cell death. This mechanism may possibly play a role in X4 HIV-associated neurodegeneration.

Astrocytoma↗
PubMed2006

Fundamentals of stem cell mobilization for the heart: prospects for treating heart disease.

Despite significant advances in the detection, prevention and treatment of congestive heart failure, it remains a leading cause of morbidity and mortality. Recent research has revealed the potential role of stem and progenitor cells in repairing and regenerating damaged myocardium. A number of pharmacological agents that mobilize these cells, including granulocyte-colony stimulating factor, statins and AMD-3100, are currently under investigation. This review summarizes the rationale behind using these agents, as well as describing the preclinical and clinical data supporting their efficacy.

Animals↗
PubMed1975

Potential carcinogenicity of food additives and contaminants.

The potential role in carcinogenesis of food additives and contaminants presents a complex problem in terms of assessing the risk to the general public. Long-term testing in laboratory animals is still the most feasible method for determining potential carcinogenicity of various chemicals. The disadvantages encountered in the present methods of animal testing are discussed and a review is made of the current status of particular food additives and contaminants under scrutiny as possible carcinogens. It is suggested that, since it may not be possible to remove all carcinogenic materials from the environment, methods to mitigate or neutralize their harmful effects should be sought. Greater cooperation is called for among food technologists, toxicologists, laboratory researchers, and epidemiologists in the decision-making process regarding the role of possibly carcinogenic additives and contaminants.

2-Acetylaminofluorene↗
PubMed1979

Use of artificial sweeteners by cancer patients.

Current daily use of artificial sweeteners (AS) and diet drinks was evaluated for 1,862 patients hospitalized for cancer and for 10,874 "control" patients hospitalized for other conditions believed not to be associated with use of these substances. The data were derived from an ongoing survey in seven countries. For cancer of most sites, the age-standardized proportion of users of AS was somewhat less than that for controls. A greater proportion of users among cancer patients than among controls was noted only for cancer of the stomach among women. Little information on urinary tract cancer was available; there were no users of AS among 13 patients with cancer of the bladder, 5 with cancer of the renal pelvis, and 2 with cancer of the ureter. There were 455 cancer patients known to have been interviewed during their initial hospitalization for the disease. Based on these cases, an age-sex-country-standardized estimate of cancer incidence for users of AS, relative to nonusers, was 1.0. Only a very small proportion of patients reported daily use of diet drinks, and the proportion of users did not differ substantially between cancer patients and controls. The present data provide virtually no support for an overall positive association of AS with cancer.

Aged↗
PubMed1987

Position of the American Dietetic Association: appropriate use of nutritive and non-nutritive sweeteners.

Moderation in the consumption of nutritive and non-nutritive sweeteners appears to be prudent advice for persons who choose to use sweeteners. The major benefit from use of sweeteners is a perceived improvement in the quality of life. Some nutritive sweeteners also provide important textural properties to many foods. Sweeteners should be used in the context of an otherwise nutritious and well-balanced diet. Excessive intake of any sweetener requires nutrition counseling for basic nutrition reasons. An individual can minimize potential risks from any one sweetener by using a variety of available sweeteners, thus ingesting less of any specific sweetener. Research into possible risks of long-term uses of non-nutritive sweeteners, either alone or in combination, should continue. It is important that the public have a choice of various non-nutritive sweeteners, with safe and reasonable guidelines on how to use each. As new sweeteners become available, they must receive the same rigorous testing to which previously approved sweeteners have been subjected.

Aspartame↗
PubMed1985

[Etiology of bladder cancer].

Multiple agents have been suggested as urinary bladder carcinogens. Of these, certain aromatic amines and some tryptophan metabolites (Anthranilic acid, 3 hydroxy Anthranilic acid) have been proved to be carcinogenic. Others are suggested but are not conclusively proved as carcinogenic agents. Various animal species have been used as experimental models for the study of induction of cancer of the bladder and substantial progress has been made in the search for etiologic factors and pathogenesis of bladder tumors. A carcinogenic model of cancer bladder induction is proposed. However, knowledge of the tumorigenesis of cancer of the bladder is still limited and fragmentary. It appears, however, that Tryptophan dysmetabolism play a major role in this field and future experimental and epidemiologic studies should take this fact into consideration.

Animals↗