Freudlsperger Christian, Thies Anka, Pfüller Uwe, Schumacher Udo
Institut für Anatomie II: Experimentelle Morphologie, Universitätsklinikum Hamburg-Eppendorf 20246 Hamburg, Germany.
Anticancer Res. 2007 Jan-Feb;27(1A):207-13.
The NFkappaB signalling pathway plays an important role in chemoresistance and decreased apoptosis. One indirect way to inhibit the NFkappaB pathway is to slow down the proteasomal degradation of its inhibitor IkappaB, thus preventing NFkappaB from translocation into the nucleus. Hence, the effect of the proteasome inhibitor bortezomib (Velcade) on the cell proliferation of the MV3, FemX-1 and G361 human melanoma cell lines and its action in combination with the PPAR-gamma agonist rosiglitazone or the mistletoe lectin ML-I, both having anti-proliferative effects on melanoma cells in single agent use, was investigated.
Proliferation of melanoma cells under the different treatment regimes over a broad concentration range (0.0001-100 microg/ml) was assessed by means of the XTT cell proliferation assay.
At a concentration of 0.1 microg/ml bortezomib significantly reduced the proliferation rate of all melanoma cells to 1-13% of the control, which was mediated through increased apoptosis and inhibition of NFkappaB expression. Furthermore, the combination of bortezomib and rosiglitazone was the most potent and increased the effectiveness against melanoma cell growth by 63-71% (compared to single use of rosiglitazone) and by 27-39% (compared to single use of bortezomib), respectively.
This combination strategy might be a promising approach for future melanoma therapy.
核因子κB（NFκB）信号通路在化疗耐药和细胞凋亡减少中起重要作用。抑制NFκB通路的一种间接方法是减缓其抑制剂IκB的蛋白酶体降解，从而阻止NFκB易位至细胞核。因此，研究了蛋白酶体抑制剂硼替佐米（万珂）对MV3、FemX-1和G361人黑色素瘤细胞系细胞增殖的影响，以及其与PPAR-γ激动剂罗格列酮或槲寄生凝集素ML-I联合使用的作用，这两种药物在单药使用时对黑色素瘤细胞均有抗增殖作用。
采用XTT细胞增殖试验评估在广泛浓度范围（0.0001-100μg/ml）内不同治疗方案下黑色素瘤细胞的增殖情况。
在浓度为0.1μg/ml时，硼替佐米显著降低了所有黑色素瘤细胞的增殖率，降至对照的1%-13%，这是通过增加细胞凋亡和抑制NFκB表达介导的。此外，硼替佐米与罗格列酮联合使用最为有效，分别使抗黑色素瘤细胞生长的效力提高了63%-71%（与单用罗格列酮相比）和27%-39%（与单用硼替佐米相比）。
这种联合策略可能是未来黑色素瘤治疗的一种有前景的方法。
