Combination of thalidomide and cisplatin in an head and neck squamous cell carcinomas model results in an enhanced antiangiogenic activity in vitro and in vivo

Abstract

Thalidomide is an immunomodulatory, antiangiogenic drug. Although there is evidence that it might be more effective in combination with chemotherapy the exact mechanism of action is unclear. Therefore, we investigated its effect in combination with metronomically applied cisplatin in a xenotransplant mouse model characteristic for advanced head and neck squamous cell carcinomas, its possible synergistic action in vitro, and which tumorderived factors might be targeted by thalidomide. Although thalidomide alone was ineffective, a combined treatment with low-dose cisplatin inhibited significant tumor growth, proliferation and angiogenesis in vivo as well as migration and tube formation of endothelial cells in vitro. Noteworthy, the latter effect was enhanced after coapplication of cisplatin in nontoxic doses. An inhibitory effect on tumor cell migration was also observed suggesting a direct antitumor effect. Although thalidomide alone did not influence cell proliferation, it augmented antiproliferative response after cisplatin application emphasizing the idea of a potentiated effect when both drugs are combined. Furthermore, we could show that antiangiogenic effects of thalidomide are related to tumor-cell derived factors including vascular endothelial growth factor, basic fibroblast growth factor, hepatocyte growth factor and Il-8 some known and with, granulocyte colony stimulating growth factor and granulocyte macrophage colony stimulating growth factor, some new target molecules of thalidomide. Altogether, our findings reveal new insights into thalidomide-mediated antitumor and antiangiogenic effects and its interaction with cytostatic drugs. ' 2007 Wiley-Liss, Inc.Key words: thalidomide; cisplatin; antiangiogenic therapy; head and neck squamous cell carcinoma Angiogenesis is a rate limiting step during tumor development.

Differentiation Therapy Exerts Antitumor Effects on Stem-like Glioma Cells

“…Tissues were enzymatically dissociated and cultivated as floating neurospheres in DMEM/F-12 medium containing 20% BIT serum-free supplement, basic fibroblast growth factor (bFGF), and epidermal growth factor at 20 ng/mL each (all Provitro). Primary human umbilical vein endothelial cells (HUVEC) were cultured as described (19). To induce differentiation, neurospheres were grown in DMEM containing 10% FCS and 10 nmol/L ATRA.…”

“…Staining of mouse tissue sections and neurospheres was carried out as described (19). Primary antibodies used were mouse antihuman CD133 (clone AC133, 4,1 μg/mL, Miltenyi), mouse antihuman nestin (1 μg/mL, R&D), mouse antihuman glial fibrillary acidic protein (GFAP; ready-to-use, Progen), mouse antihuman Ki-67 (10 μg/mL, BD Pharmingen), rat antimouse CD31 (2 μg/mL, BD Pharmingen), mouse antihuman βIII-tubulin (ascites, 1:100, Chemicon), mouse antihuman myelin basic protein myelin basic protein (culture supernatant, 1:100, Chemicon), and mouse antihuman NOTCH1 (8 μg/mL, Abcam).…”

Thalidomide–A Notorious Sedative to a Wonder Anticancer Drug

“…Bertolini and colleagues further provided the clinical evidence that thalidomide decreased the plasma levels of these angiogenic growth factors in patients with multiple myeloma or myelodysplastic syndromes or histiocytosis [28]. Such effects were also observed in other cancer types, such as lung adenocarcinoma and head and neck squamous cell carcinoma [29, 30]. In addition, Steins and co-workers demonstrated a considerable efficacy of thalidomide against acute myeloid leukemia as evidenced by that the responders for thalidomide treatment experienced hematologic improvements with increased hemoglobin and platelet counts and this effect was linked to its significant anti-angiogenic effects [31].…”

N-benzyl-5-phenyl-1H-pyrazole-3-carboxamide promotes vascular endothelial cell angiogenesis and migration in the absence of serum and FGF-2

“…HUVECs were seeded on 24-well plates coated with Matrigel at 4×10 Cell migration assay The cell migration assay was performed as described previously [16,17] . Cells were seeded on 24-well plates.…”