In vitro anti-proliferative and anti-angiogenic activities of thalidomide dithiocarbamate analogs

• Published in: International immunopharmacology Vol. 21; no. 2; pp. 283 - 292
• Main Authors: El-Aarag, Bishoy Y.A., Kasai, Tomonari, Zahran, Magdy A.H., Zakhary, Nadia I., Shigehiro, Tsukasa, Sekhar, Sreeja C., Agwa, Hussein S., Mizutani, Akifumi, Murakami, Hiroshi, Kakuta, Hiroki, Seno, Masaharu
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 01.08.2014
• Subjects: Angiogenesis; Angiogenesis Inhibitors - pharmacology; Breast Neoplasms - drug therapy; Breast Neoplasms - metabolism; Cell Line; Cell Line, Tumor; Cell Proliferation - drug effects; Female; Human Umbilical Vein Endothelial Cells; Humans; Interleukin-6 - metabolism; Interleukin-8 - metabolism; Matrix Metalloproteinase 2 - metabolism; Migration; Neovascularization, Pathologic - drug therapy; Neovascularization, Pathologic - metabolism; Nitric Oxide - metabolism; Thalidomide - pharmacology; Thalidomide dithiocarbamate analogs; Thiocarbamates - pharmacology; Tumor Necrosis Factor-alpha - metabolism; Vascular Endothelial Growth Factor A - metabolism; VEGF; Angiogenesis; NO; Thalidomide dithiocarbamate analogs; Migration; VEGF
• ISSN: 1567-5769; 1878-1705
• DOI: 10.1016/j.intimp.2014.05.007

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. •The analogs exhibited anti-proliferative action on HUVEC cells without cytotoxicity.•The analogs showed anti-angiogenicity in wound healing and tube formation assays.•IL-6, IL-8, TNF-α, VEGF165, and MMP-2 mRNA levels in MDA-MB-231 were suppressed.•The analogs may be excellent leads for the development of anti-cancer drugs.