Inhibition of 13-cis retinoic acid-induced gene expression of homeobox B7 by thalidomide.
Thalidomide and 13-cis retinoic acid (RA) show anticancer effects as sole agents or in combination with other drugs. However, induction of homeobox (HOX) gene expression by 13-cis RA may contribute to tumor progression thereby potentially limiting its efficacy. The purpose was to test if thalidomide can inhibit 13-cis RA-induced HOXB7 expression and whether thalidomide may enhance the antiproliferative effect of 13-cis RA in U343MG glioblastoma cells. Quantitative real-time PCR showed significant inhibition of 13-cis RA-induced HOXB7 expression by thalidomide with IC(50) approximately 0.1-0.2 microg/ml when given simultaneously with 13-cis RA but not when administered 18 h later (p < 0.0001). 13-cis RA alone inhibited proliferation and colony formation in a concentration-dependent manner whereas growth inhibition by thalidomide alone at 5-100 microg/ml was constant at 80-90% of controls. At 10% serum concentration, growth inhibition by a combination of the 2 drugs was additive but at 1% serum, growth inhibition was synergistic. It is concluded that thalidomide inhibits the RA-induced HOXB7 expression in glioblastoma cells and that 13-cis RA/thalidomide combinations can in principle enhance cytotoxicity. The improved cell kill induced by thalidomide is attributed to downregulation of growth stimulatory factors induced by 13-cis RA. Implications for the modus operandi of thalidomide in embryogenesis are noted.
Milanović
Dusan
D
Department of Radiation Oncology, Mannheim Medical Centre, University of Heidelberg, Mannheim, Germany.
Maier
Patrick
P
Lohr
Frank
F
Wenz
Frederik
F
Herskind
Carsten
C
D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D015153:Blotting, Western; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004357:Drug Synergism; D015870:Gene Expression / Q000187:drug effects*; D005909:Glioblastoma / Q000235:genetics / Q000378:metabolism; D018398:Homeodomain Proteins / Q000096:biosynthesis / Q000187:drug effects* / Q000235:genetics; D006801:Humans; D015474:Isotretinoin / Q000494:pharmacology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013792:Thalidomide / Q000494:pharmacology*
C490538:HOXB7 protein, human; D018398:Homeodomain Proteins; D013792:Thalidomide; D015474:Isotretinoin