The G-rich promoter and G-rich coding sequence of basic fibroblast growth factor are the targets of thalidomide in glioma.
Thalidomide is considered to be a potent antiangiogenic and immunomodulatory drug for cancer therapy. Earlier clinical studies have found that patients responding to this drug often had high plasma levels of basic fibroblast growth factor (bFGF). This cytokine is a proangiogenic factor overexpressed in many tumors and is also a regulator of limb development; hence, it might be a target of thalidomide. Using U-87 MG cell lines, we found that thalidomide, especially when encapsulated in a liposome, down-regulated the transcription and translation of the FGF-2 gene by interacting with G-rich regions present in the promoter and the internal ribosome entry site of its transcript at concentrations much lower than therapeutic serum concentrations. Thalidomide treatment also dramatically suppressed the anchorage-independent growth of U-87 MG and other glioma cells by over a thousand fold without affecting its anchorage-dependent growth, which may be accomplished by knocking down endogenous bFGF expression in these cells. Accordingly, the addition of recombinant bFGF partially restored the anchorage-independent growth of these cells. Our data suggest that by targeting the G-rich regions of bFGF, thalidomide (at 0.1 microg/mL) can reduce cellular bFGF levels and affect tumor anchorage-independent growth, the hallmark of tumorigenicity. Our results are promising for future clinical investigations using low doses of thalidomide.
Mei
Szu-Chieh
SC
Institute of Biopharmaceutical Science, School of Pharmaceutical Science, National Yang-Ming University, Shih-Pai, Taipei, Taiwan, Republic of China.
Wu
Rong-Tsun
RT
D020533:Angiogenesis Inhibitors / Q000494:pharmacology*; D001932:Brain Neoplasms / Q000378:metabolism* / Q000473:pathology; D016222:Fibroblast Growth Factor 2 / Q000235:genetics* / Q000378:metabolism; D005910:Glioma / Q000378:metabolism* / Q000473:pathology; D006147:Guanine / Q000737:chemistry; D006801:Humans; D011401:Promoter Regions, Genetic; D013792:Thalidomide / Q000494:pharmacology*; D014158:Transcription, Genetic / Q000187:drug effects
D020533:Angiogenesis Inhibitors; D016222:Fibroblast Growth Factor 2; D013792:Thalidomide; D006147:Guanine