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.

In Vivo Antitumor Activity of Phytochemical Pitc-2 Obtained From Tissue Cultured Plant Pluchea Indica on Sarcoma-180 Solid Tumor Mice Model

“…The mice treated with PITC-2 at different dose inhibit body weight, tumor weight, tumor volume, tumor inhibition ratio and also brought hematological parameters to more or less normal level which is dose-dependent. A same type of finding was observed by de Costa et al on in vivo anticancer and antiangiogenic potential of thalidomide derivatives [22]. This study also shows inhibition of body weight, tumor volume, and tumor inhibition ratio.…”

“…where A is average tumor weight in negative control and B is average in each treatment group [22]. However, in case of an ascetic tumor, peritoneal fluid was collected from the peritoneal cavity.…”

Crystal structure of 1-(cyclopentylideneamino)-3-(prop-2-en-1-yl)thiourea

“…For the biological activities of thiosemicarbazide-containing compounds, see: Hu et al (2010); da Costa et al (2015). For the synthesis of the title compound, see: Mague et al (2014).…”

A Novel Green Synthesis of Thalidomide and Analogs

“…This reemergence of thalidomide has led to a number of FDA approved derivatives including lenalidomide and pomalidomide (multiple myeloma) [3][4][5]. Currently thalidomide and its derivatives are used in the treatment of numerous diseases including Crohn [6][7][8], Leprosy [9][10][11], Graft-Versus-Host (GVHD) [12][13][14], and multiple forms of cancer [15][16][17]. They are also known to modulate the expression patterns of several proteins including TNF [18][19][20][21][22], IL1 [23][24][25][26][27], and COX2 [28][29][30][31].…”