Improvement of in vivo anticancer and antiangiogenic potential of thalidomide derivatives

• Published in: Chemico-biological interactions Vol. 239; pp. 174 - 183
• Main Authors: da Costa, Patrícia Marçal, da Costa, Marcilia Pinheiro, Carvalho, Adriana Andrade, Cavalcanti, Suellen Melo Tibúrcio, de Oliveira Cardoso, Marcos Veríssimo, de Oliveira Filho, Gevânio Bezerra, de Araújo Viana, Daniel, Fechine-Jamacaru, Francisco Vagnaldo, Leite, Ana Cristina Lima, de Moraes, Manoel Odorico, Pessoa, Claudia, Ferreira, Paulo Michel Pinheiro
• Format: Journal Article
• Language: English
• Published: Ireland Elsevier Ireland Ltd 05-09-2015
• Subjects: Angiogenesis inhibition; Angiogenesis Inhibitors - chemistry; Angiogenesis Inhibitors - pharmacology; Animals; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; Antitumor; Cell Line, Tumor - drug effects; Cell Movement - drug effects; Cell Proliferation - drug effects; Chick Embryo; Chorioallantoic Membrane - blood supply; Chorioallantoic Membrane - drug effects; Female; Human cells; Humans; Mice; Neovascularization, Pathologic - drug therapy; Phthalimide derivatives; Sarcoma 180; Structure-Activity Relationship; Thalidomide - analogs & derivatives; Thalidomide - chemistry; Toxicity; Xenograft Model Antitumor Assays; Phthalimide derivatives; Angiogenesis inhibition; Sarcoma 180; Toxicity; Human cells; Antitumor
• ISSN: 0009-2797; 1872-7786
• DOI: 10.1016/j.cbi.2015.06.037

•Thalidomide, 2a and 2b inhibited in vivo tumor growth in S180-bearing treated mice.•Assays with chorioallantoic membrane showed reduction of vascularization.•2a and 2b presented moderate and reversible toxicity on liver, kidneys and spleens.•Thiosemicarbazone group into the phthalimidic ring improved antineoplastic potential.
The strategy of antiangiogenic drugs is based on inhibiting formation of new blood vessels as alternative to limit cancer progression. In this work, we investigated the antitumor and antiangiogenic potential of eight thalidomide derivatives. Most of the molecules was not cytotoxic but 2a, 2d and 3d revealed weak antiproliferative activity on HL-60, Sarcoma 180 (S180) and normal peripheral blood mononuclear cells. Thalidomide, 2a and 2b were able to inhibit tumor growth (53.5%, 67.9% and 67.4%, respectively) in S180-bearing mice and presented moderate and reversible toxicity on liver, kidneys and spleens. Both analogs (2a and 2b) inhibited cell migration of endothelial (HUVEC) and melanoma cells (MDA/MB-435) at 50μg/mL. Immunohistochemistry labeling assays with CD-31 (PECAM-1) antibody showed microvascular density (MVD) was significantly reduced in thalidomide, 2a and 2b groups (30±4.9, 64.6±1.8 and 46.5±19.5%, respectively) (p<0.05). Neovascularization evaluated by Chorioallantoic Membrane Assay (CAM) with compounds 2a and 2b showed reduction of vessels’ number (12. 9±2.3 and 14.8±3.3%), neovascularization area (13.1±1.7 and 14.3±1.7%) and total length of vessels (9.2±1.5 and 9.9±1.9%). On the other hand, thalidomide did not alter vascularization parameters. Consequently, addition of thiosemicarbazone pharmacophore group into the phthalimidic ring improved the in vivo antitumor and antiangiogenic potential of the analogs 2a and 2b.