Characterization of TNP-470-induced modifications to cell functions in HUVEC and cancer cells.
The aim of the present work is to characterize (both in vitro and in vivo) the influence of TNP-470 on different cell functions involved in angiogenesis and, more particularly, on endothelial cell growth, cell migration and vessel formation. In addition, a possible direct anti-tumor activity was investigated. To this end, we made use in vitro of human umbilical cord endothelial vein (HUVEC) cells and two human cancer cell lines. The TNP-470 effects on the growth of cancer cell lines were compared to those of Taxol (an inhibitor of microtubule depolymerization), a cytotoxic reference which also displays strong antiogenic activity at low (non-toxic) doses. The in vitro effects were characterized on the mouse mammary MXT adenocarcinoma, on which we also characterized the influence of three clinically active anti-tumor compounds (as cytotoxic references). The purpose of this part of the study was to determine the actual TNP-470-related anti-tumor activity and to evaluate the possible toxic side-effects at the doses at which this compound induces tumor growth inhibition. These investigations were completed by analyzing the TNP-470 effects on HUVEC cell motility and in vitro and in vivo vessel formation. The results show that in vitro, TNP-470 inhibited the growth not only of HUVEC, but also of neoplastic cells. Furthermore, TNP-470 clearly inhibited in vitro endothelial cell motility (p<10(-5)). However, it had only a minor effect (p=0.02) on the formation of HUVEC cell networks on Matrigel(R). In vivo, TNP-470 was able to inhibit tumor growth (on the MXT model) at a dose (50 mg/kg) associated with toxic side-effects. Histological examination showed a significant inhibition of vessel formation (p<0.001) at high (toxic) and intermediary (non-toxic) doses (50 and 20 mg/kg). However, we also observed that TNP-470 stimulated lymphocyte proliferation. Thus, care must be taken with the TNP-470 compound in combination with other anti-tumoral agents in order to avoid certain unfortunate clinical complications.
Farinelle
S
S
Laboratory of Histopathology, Faculty of Medicine, Université Libre de Bruxelles, 808 route de Lennik, 1070 Brussels, Belgium.
Malonne
H
H
Chaboteaux
C
C
Decaestecker
C
C
Dedecker
R
R
Gras
T
T
Darro
F
F
Fontaine
J
J
Atassi
G
G
Kiss
R
R
D000230:Adenocarcinoma / Q000098:blood supply / Q000188:drug therapy / Q000473:pathology; D020533:Angiogenesis Inhibitors / Q000494:pharmacology* / Q000633:toxicity; D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology* / Q000633:toxicity; D001672:Biocompatible Materials; D002455:Cell Division / Q000187:drug effects; D002465:Cell Movement / Q000187:drug effects; D003094:Collagen; D003110:Colonic Neoplasms / Q000188:drug therapy / Q000473:pathology; D003510:Cyclohexanes; D004338:Drug Combinations; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects* / Q000254:growth & development; D005909:Glioblastoma / Q000188:drug therapy / Q000473:pathology; D006131:Growth Inhibitors / Q000494:pharmacology / Q000633:toxicity; D006801:Humans; D007797:Laminin; D008325:Mammary Neoplasms, Experimental / Q000098:blood supply* / Q000188:drug therapy* / Q000473:pathology; D051379:Mice; D009368:Neoplasm Transplantation; D009389:Neovascularization, Pathologic / Q000188:drug therapy; D000077609:O-(Chloroacetylcarbamoyl)fumagillol; D017239:Paclitaxel / Q000494:pharmacology / Q000633:toxicity; D011509:Proteoglycans; D012717:Sesquiterpenes / Q000494:pharmacology* / Q000633:toxicity; D014407:Tumor Cells, Cultured / Q000187:drug effects
D020533:Angiogenesis Inhibitors; D000903:Antibiotics, Antineoplastic; D001672:Biocompatible Materials; D003510:Cyclohexanes; D004338:Drug Combinations; D006131:Growth Inhibitors; D007797:Laminin; D011509:Proteoglycans; D012717:Sesquiterpenes; C059485:matrigel; D003094:Collagen; D017239:Paclitaxel; D000077609:O-(Chloroacetylcarbamoyl)fumagillol