title: In vitro anti-proliferative and anti-angiogenic activities of thalidomide dithiocarbamate analogs.
abstract: Inhibition of angiogenesis is currently perceived as a promising strategy in the treatment of cancer. The anti-angiogenicity of thalidomide has inspired a second wave of research on this teratogenic drug. The present study aimed to investigate the anti-proliferative and anti-angiogenic activities of two thalidomide dithiocarbamate analogs by studying their anti-proliferative effects on human umbilical vein endothelial cells (HUVECs) and MDA-MB-231 human breast cancer cell lines. Their action on the expression levels of IL-6, IL-8, TNF-α, VEGF165, and MMP-2 was also assessed. Furthermore, their effect on angiogenesis was evaluated through wound healing, migration, tube formation, and nitric oxide (NO) assays. Results illustrated that the proliferation of HUVECs and MDA-MB-231 cells was not significantly affected by thalidomide at 6.25-100μM. Thalidomide failed to block angiogenesis at similar concentrations. By contrast, thalidomide dithiocarbamate analogs exhibited significant anti-proliferative action on HUVECs and MDA-MB-231 cells without causing cytotoxicity and also showed powerful anti-angiogenicity in wound healing, migration, tube formation, and NO assays. Thalidomide analogs 1 and 2 demonstrated more potent activity to suppress expression levels of IL-6, IL-8, TNF-α, VEGF165, and MMP-2 than thalidomide. Analog 1 consistently, showed the highest potency and efficacy in all the assays. Taken together, our results support further development and evaluation of novel thalidomide analogs as anti-tumor and anti-angiogenic agents.
authors.affiliation: Chemistry Department, Faculty of Science, Menofia University, Egypt; Division of Chemistry and Biotechnology, Graduate School of Natural Science and Technology, Okayama University, Okayama 7008530, Japan.
authors.forename: Bishoy Y A
authors.initials: BY
authors.lastname: El-Aarag
authors.affiliation: Division of Chemistry and Biotechnology, Graduate School of Natural Science and Technology, Okayama University, Okayama 7008530, Japan. Electronic address: t-kasai@cc.okayama-u.ac.jp.
authors.forename: Tomonari
authors.initials: T
authors.lastname: Kasai
authors.affiliation: Chemistry Department, Faculty of Science, Menofia University, Egypt.
authors.forename: Magdy A H
authors.initials: MA
authors.lastname: Zahran
authors.affiliation: Cancer Biology Department, National Cancer Institute, Cairo University, Egypt.
authors.forename: Nadia I
authors.initials: NI
authors.lastname: Zakhary
authors.affiliation: Division of Chemistry and Biotechnology, Graduate School of Natural Science and Technology, Okayama University, Okayama 7008530, Japan.
authors.forename: Tsukasa
authors.initials: T
authors.lastname: Shigehiro
authors.affiliation: Division of Chemistry and Biotechnology, Graduate School of Natural Science and Technology, Okayama University, Okayama 7008530, Japan.
authors.forename: Sreeja C
authors.initials: SC
authors.lastname: Sekhar
authors.affiliation: Chemistry Department, Faculty of Science, Menofia University, Egypt.
authors.forename: Hussein S
authors.initials: HS
authors.lastname: Agwa
authors.affiliation: Division of Chemistry and Biotechnology, Graduate School of Natural Science and Technology, Okayama University, Okayama 7008530, Japan.
authors.forename: Akifumi
authors.initials: A
authors.lastname: Mizutani
authors.affiliation: Division of Chemistry and Biotechnology, Graduate School of Natural Science and Technology, Okayama University, Okayama 7008530, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Murakami
authors.affiliation: Division of Pharmaceutical Sciences, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama 7008530, Japan.
authors.forename: Hiroki
authors.initials: H
authors.lastname: Kakuta
authors.affiliation: Division of Chemistry and Biotechnology, Graduate School of Natural Science and Technology, Okayama University, Okayama 7008530, Japan.
authors.forename: Masaharu
authors.initials: M
authors.lastname: Seno
mesh_terms: D020533:Angiogenesis Inhibitors / Q000494:pharmacology*; D001943:Breast Neoplasms / Q000188:drug therapy / Q000378:metabolism; D002460:Cell Line; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D005260:Female; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D015850:Interleukin-6 / Q000378:metabolism; D016209:Interleukin-8 / Q000378:metabolism; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D009389:Neovascularization, Pathologic / Q000188:drug therapy* / Q000378:metabolism; D009569:Nitric Oxide / Q000378:metabolism; D013792:Thalidomide / Q000494:pharmacology*; D013859:Thiocarbamates / Q000494:pharmacology*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
chemical_list: D020533:Angiogenesis Inhibitors; D015850:Interleukin-6; D016209:Interleukin-8; D013859:Thiocarbamates; D014409:Tumor Necrosis Factor-alpha; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; D009569:Nitric Oxide; D013792:Thalidomide; D020778:Matrix Metalloproteinase 2
keywords: Angiogenesis; Migration; NO; Thalidomide dithiocarbamate analogs; VEGF