title: Improvement of in vivo anticancer and antiangiogenic potential of thalidomide derivatives.
abstract: 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.
authors.affiliation: Department of Physiology and Pharmacology, School of Medicine, Federal University of Ceará, 60.430-270 Fortaleza, Ceará, Brazil.
authors.forename: Patrícia Marçal
authors.initials: PM
authors.lastname: da Costa
authors.affiliation: Department of Pharmacy, Federal University of Piauí, 64049-550 Teresina, Brazil.
authors.forename: Marcilia Pinheiro
authors.initials: MP
authors.lastname: da Costa
authors.affiliation: Department of Pharmacy/Postgraduate Program in Health Sciences, Federal University of Sergipe, 49400-000 Lagarto, Sergipe, Brazil.
authors.forename: Adriana Andrade
authors.initials: AA
authors.lastname: Carvalho
authors.affiliation: Department of Pharmaceutical Sciences, Federal University of Pernambuco, 50670-901 Recife, Pernambuco, Brazil.
authors.forename: Suellen Melo Tibúrcio
authors.initials: SM
authors.lastname: Cavalcanti
authors.affiliation: Department of Pharmaceutical Sciences, Federal University of Pernambuco, 50670-901 Recife, Pernambuco, Brazil.
authors.forename: Marcos Veríssimo
authors.initials: MV
authors.lastname: de Oliveira Cardoso
authors.affiliation: Department of Pharmaceutical Sciences, Federal University of Pernambuco, 50670-901 Recife, Pernambuco, Brazil.
authors.forename: Gevânio Bezerra
authors.initials: GB
authors.lastname: de Oliveira Filho
authors.affiliation: School of Veterinary Medicine, State University of Ceará, 60740-000 Fortaleza, Ceará, Brazil.
authors.forename: Daniel
authors.initials: D
authors.lastname: de Araújo Viana
authors.affiliation: Department of Physiology and Pharmacology, School of Medicine, Federal University of Ceará, 60.430-270 Fortaleza, Ceará, Brazil.
authors.forename: Francisco Vagnaldo
authors.initials: FV
authors.lastname: Fechine-Jamacaru
authors.affiliation: Department of Pharmaceutical Sciences, Federal University of Pernambuco, 50670-901 Recife, Pernambuco, Brazil.
authors.forename: Ana Cristina Lima
authors.initials: AC
authors.lastname: Leite
authors.affiliation: Department of Physiology and Pharmacology, School of Medicine, Federal University of Ceará, 60.430-270 Fortaleza, Ceará, Brazil.
authors.forename: Manoel Odorico
authors.initials: MO
authors.lastname: de Moraes
authors.affiliation: Department of Physiology and Pharmacology, School of Medicine, Federal University of Ceará, 60.430-270 Fortaleza, Ceará, Brazil; Fundação Oswaldo Cruz (FIOCRUZ), 60180-900 Fortaleza, Ceará, Brazil.
authors.forename: Claudia
authors.initials: C
authors.lastname: Pessoa
authors.affiliation: Laboratory of Experimental Cancerology, Department of Biophysics and Physiology, Postgraduate in Pharmaceutical Sciences, Federal University of Piauí, 64049-550 Teresina, Brazil. Electronic address: pmifepe@yahoo.com.br.
authors.forename: Paulo Michel Pinheiro
authors.initials: PM
authors.lastname: Ferreira
mesh_terms: D020533:Angiogenesis Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry* / Q000494:pharmacology*; D045744:Cell Line, Tumor / Q000187:drug effects; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002642:Chick Embryo; D049033:Chorioallantoic Membrane / Q000098:blood supply / Q000187:drug effects; D005260:Female; D006801:Humans; D051379:Mice; D009389:Neovascularization, Pathologic / Q000188:drug therapy; D013329:Structure-Activity Relationship; D013792:Thalidomide / Q000031:analogs & derivatives / Q000737:chemistry*; D023041:Xenograft Model Antitumor Assays
chemical_list: D020533:Angiogenesis Inhibitors; D000970:Antineoplastic Agents; D013792:Thalidomide
keywords: Angiogenesis inhibition; Antitumor; Human cells; Phthalimide derivatives; Sarcoma 180; Toxicity