title: Oral administration of pyrrolidine dithiocarbamate (PDTC) inhibits VEGF expression, tumor angiogenesis, and growth of breast cancer in female mice.
abstract: The progression of breast cancer is associated with oxidative stress.  However, the effects of pyrrolidine dithiocarbamate (PDTC), a known antioxidant, on the development of breast cancer are poorly understood.  The present study evaluates the effects of PDTC on tumor growth, the expression of vascular endothelial growth factor (VEGF), and angiogenesis of breast cancer in female mice.  Eight week old female mice (C57BL/6J) were given PDTC at 100 to 200 mg/kg/day for 3 weeks (n=10).  The control mice received regular drinking water only.  In the 2nd wk, 5x10^5 E0771 (mouse breast cancer) cells were injected in the pad of the fourth mammary gland of the mice.  Tumor size was monitored using dial calipers.  At the end of the experiment, the tumors were isolated and measured for tumor size, intratumoral microvessel (IM) density using CD31 immunohistochemistry staining, NFκB activation using EMSA, and VEGF protein levels using ELISA.  PDTC treatment caused a significant decrease in tumor weight compared to the control (0.64±0.22 vs. 1.43±0.31 g; n=8; P< 0.01), and a significant decrease in IM density (66.1±5.3 vs. 84.2±9.4 IM# /mm^2; P< 0.01).  There was a significant decrease in tissue protein levels of VEGF (22.6±2.1 vs. 32.4±2.6 pg/mg) and a 43% reduction NFκB activation in the breast tumors of mice treated with PDTC compared to the control group (P< 0.01).  Western blot indicated that estrogen receptor-α (ERα), VEGF receptor-1 (Flt-1), and VEGF receptor-2 (Flk-1) were expressed in E0771 cells.  VEGF receptor inhibitor SU5416 and PDTC synergistically suppressed the proliferation of E0771 cells.  PDTC also significantly inhibited the migration of cultured E0771 cells.  These results support the hypothesis that PDTC suppresses tumor angiogenesis, growth, and migration of breast cancer via inhibiting autocrine and paracrine effects of VEGF through the reduction of NFκB activation and VEGF expression.
authors.affiliation: Department of Physiology & Biophysics, University of Mississippi Medical Center Jackson, MS 39216, USA. jgu@physiology.umsmed
authors.forename: Jian-Wei
authors.initials: JW
authors.lastname: Gu
authors.forename: Emily
authors.initials: E
authors.lastname: Young
authors.forename: Brandi
authors.initials: B
authors.lastname: Busby
authors.forename: Jordan
authors.initials: J
authors.lastname: Covington
authors.forename: James W
authors.initials: JW
authors.lastname: Johnson
mesh_terms: D020533:Angiogenesis Inhibitors / Q000008:administration & dosage; D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage*; D001943:Breast Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D004357:Drug Synergism; D047628:Estrogen Receptor alpha / Q000235:genetics; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D007211:Indoles / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D016328:NF-kappa B / Q000037:antagonists & inhibitors; D009389:Neovascularization, Pathologic / Q000188:drug therapy / Q000378:metabolism*; D011758:Pyrroles / Q000494:pharmacology; D011759:Pyrrolidines / Q000008:administration & dosage*; D013859:Thiocarbamates / Q000008:administration & dosage*; D047368:Tumor Burden / Q000187:drug effects; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics / Q000378:metabolism*; D040281:Vascular Endothelial Growth Factor Receptor-1 / Q000037:antagonists & inhibitors / Q000378:metabolism; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000037:antagonists & inhibitors / Q000378:metabolism
chemical_list: D020533:Angiogenesis Inhibitors; D000970:Antineoplastic Agents; D047628:Estrogen Receptor alpha; D007211:Indoles; D016328:NF-kappa B; D011758:Pyrroles; D011759:Pyrrolidines; D013859:Thiocarbamates; D042461:Vascular Endothelial Growth Factor A; C020972:pyrrolidine dithiocarbamic acid; C116890:Semaxinib; D040281:Vascular Endothelial Growth Factor Receptor-1; D040301:Vascular Endothelial Growth Factor Receptor-2