Impact of cellular folate status and epidermal growth factor receptor expression on BCRP/ABCG2-mediated resistance to gefitinib and erlotinib.
Impact of cellular folate status and epidermal growth factor receptor expression on BCRP/ABCG2-mediated resistance to gefitinib and erlotinib.
复制标题
DOI：
10.1038/sj.bjc.6604980
复制
发表时间：
2009-04-07
影响因子：
8.8
通讯作者：
Peters, G. J.
中科院分区：
文献类型：
--
作者：
Lemos, C.;Kathmann, I.;Giovannetti, E.;Calhau, C.;Jansen, G.;Peters, G. J.
在两种人结肠癌细胞株WiDR和Caco-2中，研究了叶酸状态对乳腺癌耐药蛋白(BCRP)介导的表皮生长因子受体(EGFR)靶向药物吉非替尼(Gefitinib)和厄洛替尼(Erlotinib)耐药的影响，后者由于EGFR的高表达而对这些药物表现出更高的敏感性。在低叶酸(LF)条件下生长的Caco-2LF/LV细胞与高叶酸(HF)条件下生长的Caco-2LF/LV细胞相比，BCRP蛋白表达增加，这与Gefitinib耐药1.8倍有关。值得注意的是，BCRP特异性抑制剂Ko143完全逆转了这一表型。与HF细胞相比，WiDR LF细胞的BCRP表达也略有增加，但对吉非替尼的敏感性没有差异。Caco-2 LF/LV和WiDR LF细胞对Erlotinib的耐药性分别是HF细胞的2.4倍和2.3倍，而HF细胞似乎与BCRP无关，因为Ko143对Erlotinib活性没有影响。总之，我们的数据表明，在表达EGFR的Caco-2细胞中，BCRP是吉非替尼耐药的决定因素之一，但不是厄洛替尼耐药的决定因素之一。除此之外，叶酸耗竭可通过依赖或不依赖BCRP调节的机制引起吉非替尼和埃洛替尼活性的进一步降低。
The effect of folate status on breast cancer resistance protein (BCRP)-mediated drug resistance to epidermal growth factor receptor (EGFR)-targeted drugs, such as gefitinib and erlotinib, was investigated in two human colon cancer cell lines, WiDr and Caco-2, of which the latter displayed greater sensitivity to these drugs due to high EGFR expression. Caco-2 LF/LV cells, growing under low-folate (LF) conditions, showed increased BCRP protein expression compared with the high-folate (HF) counterpart, which was associated with 1.8-fold resistance to gefitinib. Of note, the BCRP-specific inhibitor Ko143 completely reverted this phenotype. WiDr LF cells also showed slightly increased BCRP expression compared with the HF cells, but no differences in gefitinib sensitivity were observed. Both Caco-2 LF/LV and WiDr LF cells showed 2.4- and 2.3-fold resistance to erlotinib, respectively, compared with their HF counterparts, which mechanistically seemed BCRP unrelated, as Ko143 had no effect on erlotinib activity. In conclusion, our data suggest that in EGFR-expressing Caco-2 cells, BCRP is one of the determinants of gefitinib resistance but not of erlotinib resistance. Beyond this, folate depletion can provoke an additional decrease in gefitinib and erlotinib activity by mechanisms dependent or independent of BCRP modulation.
登录
查看更多内容
影响因子：
11.4
作者：
Brendel, C.;Scharenberg, C.;Neubauer, A.
通讯作者：
Neubauer, A.
影响因子：
6.4
作者：
Lemos, Clara;Kathmann, Ietje;Peters, Godefridus J.
通讯作者：
Peters, Godefridus J.
影响因子：
11.2
作者：
Nakamura, Y;Oka, M;Kohno, S
通讯作者：
Kohno, S
影响因子：
11.2
作者：
Shi, Zhi;Peng, Xing-Xiang;Chen, Zhe-Sheng
通讯作者：
Chen, Zhe-Sheng
影响因子：
11.2
作者：
Houghton, PJ;Germain, GS;Traxler, P
通讯作者：
Traxler, P