Adwan Hassan, Bäuerle Tobias J, Berger Martin R
Unit of Toxicology and Chemotherapy, Deutsches Krebsforschungszentrum Heidelberg, Im Neuenheimer Feld 280, 69120 Heidelberg, Germany.
Cancer Gene Ther. 2004 Feb;11(2):109-20. doi: 10.1038/sj.cgt.7700659.
Osteopontin (OPN), bone sialoprotein (BSPII), and osteonectin (ON) belong to a family of glycoproteins, which have been linked to cancer metastasis and progression. Here, we report on the selection of antisense oligonucleotides (ASOs), which are effective in reducing their protein levels. In human MDA-MB-231 breast cancer cells, the maximum inhibition of protein expression ranged from 84% (OPN) to 75% (BSPII) and 70% (ON). Erucylphospho-NNN-trimethylpropanolamine (ErPC3) was used as positive control and combination partner. Exposure to ErPC3 inhibited colony formation of MDA-MB-231 cells by 11% (10 microM), 45% (14 microM) and 78% (20 microM). The clonogenicity of breast cancer cells was reduced by 15%, 11%, 8% (5 microM), 39%, 19%, 14% (10 microM) and 46%, 39%, 21% (20 microM) in response to ASO-OPN-04, ASO-BSPII-06 and ASO-ON-03, respectively. Combination of ErPC3 with the ASOs caused additive combination effects. Pre-exposure to the ASOs, but not to the NSO, inhibited formation of osteolytic metastasis in three of four (ASO-OPN-04, P<0.03) and two of four (ASO-BSPII-06) nude rats, and reduced metastasis lesions significantly (T/C%=4.3 and 9.1, P=0.05, respectively). We conclude that downregulation of OPN and BSPII reduces colony formation of MDA-MB-231 cells and formation of osteolytic metastasis in nude rats.
骨桥蛋白（OPN）、骨唾液蛋白（BSPII）和骨连接蛋白（ON）属于糖蛋白家族，它们与癌症转移和进展有关。在此，我们报告了对反义寡核苷酸（ASO）的筛选，这些反义寡核苷酸在降低其蛋白水平方面是有效的。在人MDA-MB-231乳腺癌细胞中，蛋白表达的最大抑制率范围为84%（OPN）至75%（BSPII）和70%（ON）。芥酰磷-NNN-三甲基丙醇胺（ErPC3）用作阳性对照和联合用药伙伴。暴露于ErPC3可使MDA-MB-231细胞的集落形成分别受到11%（10微摩尔）、45%（14微摩尔）和78%（20微摩尔）的抑制。响应ASO-OPN-04、ASO-BSPII-06和ASO-ON-03，乳腺癌细胞的克隆形成能力分别降低了15%、11%、8%（5微摩尔）、39%、19%、14%（10微摩尔）和46%、39%、21%（20微摩尔）。ErPC3与ASO联合使用产生相加联合效应。预先暴露于ASO而非NSO，在四只裸鼠中有三只（ASO-OPN-04，P<0.03）和四只中有两只（ASO-BSPII-06）抑制了溶骨性转移的形成，并显著减少了转移病灶（T/C%分别为4.3和9.1，P=0.05）。我们得出结论，下调OPN和BSPII可降低MDA-MB-231细胞的集落形成以及裸鼠溶骨性转移的形成。
