A combination treatment with DNA methyltransferase inhibitors and suramin decreases invasiveness of breast cancer cells.
A combination treatment with DNA methyltransferase inhibitors and suramin decreases invasiveness of breast cancer cells.
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DOI：
10.1007/s10549-014-2857-2
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发表时间：
2014-02
影响因子：
3.8
通讯作者：
Storz, Peter
中科院分区：
文献类型：
--
作者：
Borges, Sahra;Doeppler, Heike R.;Storz, Peter
浸润性乳腺癌患者的治疗仍然是一个主要问题，因为获得对传统化疗的耐药性。在这里，我们提出了一种新的治疗策略，将DNA甲基转移酶抑制剂（DMTIs）与苏拉明联合使用。在高侵袭性乳腺癌细胞系MDA-MB-231、BT-20和HCC1954或对照细胞中，测定苏拉明或联合DMTIs治疗的细胞毒性作用。此外，在三维细胞培养实验中确定了对细胞侵袭的影响。Western blotting显示dmti介导的蛋白激酶D1 （PKD1）表达上调。在体外和细胞中测定苏拉明对PKD1活性的影响。3D细胞培养实验证明了PKD1在介导这种联合治疗对细胞侵袭的影响中的重要性。一项主要的动物实验证明PKD1对乳腺癌的生长至关重要。我们表明，当联合使用苏拉明和DMTIs时，会损害乳腺癌细胞的侵袭性表型。我们发现PKD1，一种以前被描述为肿瘤细胞侵袭抑制因子的激酶，是fda批准的两种药物的界面，因为观察到的加性效应是由于dmi介导的PKD1的再表达和苏拉明诱导的激活。我们的数据揭示了一种机制，即无毒剂量的苏拉明和DMTIs联合治疗可能对侵袭性多药耐药乳腺癌患者有治疗益处。
The treatment of patients with invasive breast cancer remains a major issue because of the acquisition of drug resistance to conventional chemotherapy. Here we propose a new therapeutic strategy by combining DNA methyltransferase inhibitors (DMTIs) with suramin. Cytotoxic effects of suramin or combination treatment with DMTIs were determined in highly invasive breast cancer cell lines MDA-MB-231, BT-20 and HCC1954, or control cells. In addition, effects on cell invasion were determined in 3-dimensional cell culture assays. DMTI-mediated upregulation of Protein Kinase D1 (PKD1) expression was shown by Western blotting. Effects of suramin on PKD1 activity was determined in vitro and in cells. The importance of PKD1 in mediating the effects of such combination treatment in cell invasion was demonstrated using 3D cell culture assays. A proof of principal animal experiment was performed showing that PKD1 is critical for breast cancer growth. We show that when used in combination, suramin and DMTIs impair the invasive phenotype of breast cancer cells. We show that PKD1, a kinase that previously has been described as a suppressor of tumor cell invasion, is an interface for both FDA-approved drugs, since the additive effects observed are due to DMTI-mediated re-expression and suramin-induced activation of PKD1. Our data reveal a mechanism of how a combination treatment with non-toxic doses of suramin and DMTIs may be of therapeutic benefit for patients with aggressive, multi-drug resistant breast cancer.
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影响因子：
8.8
作者：
Danesi, R;Del Bianchi, S;Soldani, P;Campagni, A;La Rocca, R V;Myers, C E;Paparelli, A;Del Tacca, M
通讯作者：
Del Tacca, M
DOI：
10.1186/bcr2232
发表时间：
2009
期刊：
Breast cancer research : BCR
影响因子：
--
作者：
Eiseler T;Döppler H;Yan IK;Goodison S;Storz P
通讯作者：
Storz P
影响因子：
21.3
作者：
Eiseler T;Döppler H;Yan IK;Kitatani K;Mizuno K;Storz P
通讯作者：
Storz P
DOI：
10.1016/s1054-3589(08)60486-x
发表时间：
1978-01-01
期刊：
Advances in pharmacology and chemotherapy
影响因子：
--
作者：
Hawking, F
通讯作者：
Hawking, F
DOI：
10.1016/s0006-291x(03)01161-6
发表时间：
2003-07-25
影响因子：
3.1
作者：
Jaggi, M;Rao, PS;Balaji, KC
通讯作者：
Balaji, KC