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Microenvironmental effects limit efficacy of thymoquinone treatment in a mouse model of ovarian cancer.
Wilson AJ, Saskowski J, Barham W, Khabele D, Yull F
(2015) Mol Cancer 14: 192
MeSH Terms: Animals, Antinematodal Agents, Apoptosis, Benzoquinones, Cell Line, Tumor, Clodronic Acid, Disease Models, Animal, Female, Macrophages, Mice, Mice, Inbred C57BL, NF-kappa B, Ovarian Neoplasms
Show Abstract · Added January 26, 2016
BACKGROUND - Ovarian cancer is the most lethal gynecologic malignancy, with limited treatment options for chemoresistant disease. An important link between inflammation and peritoneal spread of ovarian cancer is NF-κB signaling. Thymoquinone (TQ) exerts multiple anti-tumorigenic cellular effects, including NF-κB inhibition. We aimed to investigate the therapeutic potential of TQ in an established murine syngeneic model of ovarian cancer.
METHODS - ID8-NGL mouse ovarian cancer cells stably expressing an NF-κB reporter transgene were injected intra-peritoneally into C57BL/6 mice, and mice were treated with TQ or vehicle for 10 or 30 days. TQ was combined with the macrophage depleting drug, liposomal clodronate, in selected experiments. Effects on peritoneal tumor burden were measured by volume of ascites, number of peritoneal implants and mesenteric tumor mass. NF-κB reporter activity and markers of proliferation and apoptosis were measured in tumors and in confirmatory in vitro experiments. Protein or mRNA expression of M1 (anti-tumor) and M2 (pro-tumor) macrophage markers, and soluble cytokine profiles, were examined from harvested ascites fluid, peritoneal lavages and/or tumor sections. 2-tailed Mann-Whitney tests were used for measuring differences between groups in in vivo experiments.
RESULTS - Consistent with its effects in vitro, TQ reduced proliferation and increased apoptosis in ID8-NGL tumors after 10 and 30 day treatment. Prolonged TQ treatment did not significantly alter tumor number or mass compared to vehicle, but rather exerted an overall deleterious effect by stimulating ascites formation. Increased ascites was accompanied by elevated NF-κB activity in tumors and macrophages, increased pro-tumor M2 macrophages and expression of pro-tumorigenic soluble factors such as VEGF in ascites fluid, and increased tumor infiltration of M2 macrophages. In contrast, a 10 day exposure to TQ produced no ascites, and reduced tumor NF-κB activity, M2 macrophages and soluble VEGF levels. Peritoneal macrophage depletion by clodronate significantly reduced tumor burden. However, TQ-stimulated ascites was further enhanced by co-treatment with clodronate, with macrophages present overwhelmingly of the M2 phenotype.
CONCLUSIONS - Our findings show that pro-tumorigenic microenvironmental effects limited the efficacy of TQ in a syngeneic mouse model of ovarian cancer, and provide caution regarding its potential use in clinical trials in ovarian cancer patients.
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13 MeSH Terms
High prevalence of soil-transmitted helminths in Western Kenya: failure to implement deworming guidelines in rural Nyanza Province.
Riesel JN, Ochieng' FO, Wright P, Vermund SH, Davidson M
(2010) J Trop Pediatr 56: 60-2
MeSH Terms: Adolescent, Age Factors, Animals, Antinematodal Agents, Child, Feces, Female, Guidelines as Topic, Helminthiasis, Helminths, Humans, Kenya, Male, Mebendazole, Parasite Egg Count, Prevalence, Rural Population, Schools, Sex Factors, Soil, Students
Show Abstract · Added March 5, 2014
Soil-transmitted helminth (STH) infections affect an estimated 2 billion people world wide. Children experience the greatest morbidity, limiting their potential in academic and physical endeavors. Our study assessed the prevalence of STH infections in primary school-aged children in a rural village in the Nyanza Province of Kenya. Over two-thirds (68%) of the sampled population tested positive using a direct smear microscopic analysis of single stool samples. Only heavy worm infections would be detected with this technique; thus 68% is a minimum estimate of prevalence. Prior to our study, there were no deworming programs in this village, despite WHO and Kenyan government guidelines supporting regular deworming programs. Our study demonstrates the significant burden of STH infections in a rural Kenyan village and highlights the need for deworming programs in similar venues. We also demonstrate that with basic infrastructure and community involvement, regular deworming can be implemented effectively in remote, rural communities.
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21 MeSH Terms
Epidermal growth factor receptor dependence in human tumors: more than just expression?
Arteaga CL
(2002) Oncologist 7 Suppl 4: 31-9
MeSH Terms: Antinematodal Agents, Dimerization, ErbB Receptors, Gefitinib, Gene Expression Regulation, Neoplastic, Genes, erbB-2, Humans, Ligands, Mutation, Neoplasms, Protein-Tyrosine Kinases, Quinazolines, Receptor Cross-Talk, Signal Transduction
Show Abstract · Added March 5, 2014
The epidermal growth factor receptor (EGFR) is a rational target for antitumor strategies. EGFR signaling causes increased proliferation, decreased apoptosis, and enhanced tumor cell motility and neo-angiogenesis. The EGFR is expressed or highly expressed in a variety of human tumors of epithelial origin. ZD1839 (Iressa) is an orally active, selective EGFR tyrosine kinase inhibitor, which blocks signal transduction pathways implicated in proliferation and survival of cancer cells. The lack of a consistent method of evaluating levels of EGFR has caused a disparity in reports of the EGFR as a prognostic factor; however, for some tumors, EGFR is a strong prognostic indicator associated with more aggressive disease and reduced survival. So far, no clear association between EGFR levels and response to EGFR-targeted agents has been found. Preclinical studies with ZD1839 have noted a relationship between the two in some cases, but not others. EGFR signaling may be increased by a number of mechanisms in addition to high expression levels of EGFR, including receptor mutations, heterodimerization with other members of this receptor family such as HER2 (erbB2), increased expression of (autocrine/ paracrine) ligands, and alterations in molecules that control receptor signaling output. Each of these components could be assessed to give an indication of the magnitude of EGFR signal amplification. Evaluation of signaling components downstream from EGFR should provide information on the activation of the EGFR pathway. Until EGFR-based assays predictive of a response to receptor-targeted therapies are available, there is no clear justification for stratifying patients by EGFR status or excluding patients with low EGFR levels from trials with ZD1839 or other EGFR inhibitors.
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14 MeSH Terms
DNA-glutathione adducts derived from vic-dihaloalkanes: mechanisms of mutagenesis.
Guengerich FP, Humphreys WG, Kim DH, Oida T, Cmarik JL
(1990) Princess Takamatsu Symp 21: 101-7
MeSH Terms: Alkylation, Animals, Antinematodal Agents, DNA, DNA Damage, Dose-Response Relationship, Drug, Ethylene Dibromide, Glutathione, Humans, Mutagenesis, Mutagenicity Tests, Propane, Rats, Salmonella typhimurium
Show Abstract · Added March 5, 2014
The conjugation of the prototype dihaloalkane ethylene dibromide (EDB) with glutathione (GSH) yields S-(2-bromoethyl)GSH, which gives rise to S-[2-(N7-guanyl)ethyl]GSH as the major DNA adduct (greater than or equal to 95%). All reaction steps have SN2 character. Another minor DNA and RNA adduct is S-[2-(N1-adenyl)ethyl]GSH, formed in vitro and in vivo. These adducts have similar half-lives in vivo. Enhancement of GSH conjugation or inhibition of cytochrome P-450 IIE1 oxidation enhances DNA adduct levels in vivo and GSH depletion lowers levels. The mercapturic acid N-acetyl-S-[2-(N7-guanyl)ethyl]cysteine is excreted in urine and may find use as a biomarker. A series of compounds of the general structure RSCH2CH2Cl has been used to alkylate Salmonella typhimurium TA100. The ratio of (guanyl) base-pair mutations to N7-guanyl adducts varies dramatically, with S-(2-chloroethyl)GSH apparently producing the most potent guanyl adduct. This mutagenicity is not due to SOS response or alkylation specificity. Physical studies with modified oligonucleotides indicate that the N7-guanyl substitution weakens G-C pairing but does not in itself alter the selectivity of pairing to C in an isolated oligomer.
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14 MeSH Terms