Thalidomide inhibits growth of tumors through COX-2 degradation independent of antiangiogenesis.
Thalidomide is an antiangiogenic drug and is clinically useful in a number of cancers. However, the molecular mechanism by which thalidomide exerts its antitumor effects is poorly understood. This study was designed to clarify the relationship between antiangiogenesis and antitumor effects of thalidomide and to explore the molecular mechanism for its antitumor activity. We evaluated the effects of thalidomide on the growth of human tumor cells expressing (MCF-7 and HL-60) or not expressing (HeLa and K562) COX-2 in vitro. We also studied the effects of thalidomide on COX-1, COX-2 or bcl-2 expression, TNFalpha, VEGF, GSH and cytochrome c in these cells. Thalidomide could inhibit tumor growth in a concentration-dependent manner in MCF-7 and HL-60; its IC50s for them were 18.36+/-2.34 and 22.14+/-2.15 microM, respectively, while this effect was not observed in HeLa and K562. Thalidomide reduced COX-2 expression accompanied by a decrease of bcl-2 protein, TNFalpha, VEGF, GSH and an increased cytochrome c, but had no effect on that of COX-1, in MCF-7 and HL-60. Moreover, cells not expressing COX-2 were insensitive to the growth-inhibitory and effects on cytokines of thalidomide. In our mouse xenograft model of OVCAR-3 and HCT-8, we found that thalidomide could decrease intratumoral microvessel density in both tumors; it exerted antitumor effects only on OVCAR-3 expressing COX-2 but did not on HCT-8 not expressing COX-2. Effect of thalidomide on COX-1 and COX-2 in vivo was consistent with that of in vitro. These results demonstrated that thalidomide might inhibit growth of tumors through COX-2 degradation independent of antiangiogenesis.
Department of Pharmacology, Pharmacy College of He-nan University, Kaifeng 475001, He-nan, China. kfdgi@sohu.com
Gang-Jun
GJ
Du
Hai-Hong
HH
Lin
Qi-Tai
QT
Xu
Min-Wei
MW
Wang
D020533:Angiogenesis Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D015153:Blotting, Western; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D051546:Cyclooxygenase 2 / Q000378:metabolism*; D045304:Cytochromes c / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D005260:Female; D005978:Glutathione / Q000378:metabolism; D018922:HL-60 Cells; D006367:HeLa Cells; D006801:Humans; D020014:K562 Cells; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009389:Neovascularization, Pathologic / Q000201:enzymology / Q000517:prevention & control; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D013792:Thalidomide / Q000494:pharmacology* / Q000627:therapeutic use; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays / Q000379:methods
D020533:Angiogenesis Inhibitors; D000970:Antineoplastic Agents; D019253:Proto-Oncogene Proteins c-bcl-2; D014409:Tumor Necrosis Factor-alpha; D042461:Vascular Endothelial Growth Factor A; D013792:Thalidomide; D045304:Cytochromes c; D051546:Cyclooxygenase 2; D005978:Glutathione