4-IBP, a sigma1 receptor agonist, decreases the migration of human cancer cells, including glioblastoma cells, in vitro and sensitizes them in vitro and in vivo to cytotoxic insults of proapoptotic and proautophagic drugs.
Although the molecular function of sigma receptors has not been fully defined and the natural ligand(s) is still not known, there is increasing evidence that these receptors and their ligands might play a significant role in cancer biology. 4-(N-benzylpiperidin-4-yl)-4-iodobenzamide (4-IBP), a selective sigma1 agonist, has been used to investigate whether this compound is able to modify: 1) in vitro the migration and proliferation of human cancer cells; 2) in vitro the sensitivity of human glioblastoma cells to cytotoxic drugs; and 3) in vivo in orthotopic glioblastoma and non-small cell lung carcinoma (NSCLC) models the survival of mice co-administered cytotoxic agents. 4-IBP has revealed weak antiproliferative effects on human U373-MG glioblastoma and C32 melanoma cells but induced marked concentration-dependent decreases in the growth of human A549 NSCLC and PC3 prostate cancer cells. The compound was also significantly antimigratory in all four cancer cell lines. This may result, at least in U373-MG cells, from modifications to the actin cytoskeleton. 4-IBP modified the sensitivity of U373-MG cells in vitro to proapoptotic lomustin and proautophagic temozolomide, and markedly decreased the expression of two proteins involved in drug resistance: glucosylceramide synthase and Rho guanine nucleotide dissociation inhibitor. In vivo, 4-IBP increased the antitumor effects of temozolomide and irinotecan in immunodeficient mice that were orthotopically grafted with invasive cancer cells.
Mégalizzi
Véronique
V
Laboratoire de Toxicologie, Institut de Pharmacie, Université Libre de Bruxelles, Brussels, Belgium.
Mathieu
Véronique
V
Mijatovic
Tatjana
T
Gailly
Philippe
P
Debeir
Olivier
O
De Neve
Nancy
N
Van Damme
Marc
M
Bontempi
Gianluca
G
Haibe-Kains
Benjamin
B
Decaestecker
Christine
C
Kondo
Yasuko
Y
Kiss
Robert
R
Lefranc
Florence
F
D000199:Actins / Q000737:chemistry; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D001343:Autophagy / Q000187:drug effects*; D001549:Benzamides / Q000494:pharmacology*; D002118:Calcium / Q000378:metabolism; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects*; D004721:Endoplasmic Reticulum / Q000187:drug effects; D005260:Female; D005909:Glioblastoma / Q000188:drug therapy* / Q000473:pathology; D020730:Guanine Nucleotide Dissociation Inhibitors / Q000502:physiology; D006801:Humans; D051379:Mice; D009368:Neoplasm Transplantation; D010880:Piperidines / Q000494:pharmacology*; D017480:Receptors, sigma / Q000819:agonists* / Q000502:physiology; D014183:Transplantation, Heterologous; D062947:rho-Specific Guanine Nucleotide Dissociation Inhibitors
D000199:Actins; D000970:Antineoplastic Agents; D001549:Benzamides; D020730:Guanine Nucleotide Dissociation Inhibitors; D010880:Piperidines; D017480:Receptors, sigma; D062947:rho-Specific Guanine Nucleotide Dissociation Inhibitors; C088152:N-(N-benzylpiperidin-4-yl)-4-iodobenzamide; D002118:Calcium