Duan Zhenfeng, Choy Edwin, Jimeno Jose Maria, Cuevas Carmen Del Maria, Mankin Henry J, Hornicek Francis J
Sarcoma Biology Laboratory, Center for Sarcoma and Connective Tissue Oncology, Massachusetts General Hospital, 100 Blossom St. Jackson 1106, Boston, MA 02114, USA.
Cancer Chemother Pharmacol. 2009 May;63(6):1121-9. doi: 10.1007/s00280-008-0843-2. Epub 2008 Oct 1.
ET-743 (Yondelis, trabectedin) and PM00104 (Zalypsis) are marine derived compounds which demonstrate anti-tumor activity. The present study was performed to elucidate the relationship between the expression of ABCB1/MDR1 and ABCC1/MRP1 with resistance to either ET-743 or PM00104.
We evaluate the association between expression of Pgp1, MRP1, and BCRP proteins and ET-743 or PM00104 resistance in a large panel of multi-drug resistant cell lines derived from histologically unrelated human tumors that were selected with paclitaxel, doxorubicin, cisplatin, mitoxantrane, or gemcitibine.
Paclitaxel selected resistant cell lines expressed high levels of ABCB1 (but not ABCC1 or ABCG2/BCRP) did not demonstrate cross-resistance to either ET-743 or PM00104. In contrast, the doxorubicin selected resistant cell lines also expressed high level of ABCB1 (but not ABCC1 or ABCG2) but did demonstrate significant cross-resistance to both ET-743 and PM00104. The paclitaxel selected cell lines demonstrated cross-resistance to doxorubicin, vincristine, and mitoxantrane, while most of the above doxorubicin selected cell lines demonstrated cross-resistance to paclitaxel and vincristine, but not to mitoxantrane. On the contrary, cisplatin and gemcitabine selected cell lines demonstrated no cross-resistance to paclitaxel, doxorubicin, ET-743, or PM00104. siRNA down-regulation of ABCB1 expression in doxorubicin selected cell lines caused partial sensitization to both doxorubicin and paclitaxel but not to either ET-743 or PM00104.
These results indicate that cell lines selected for resistance to either paclitaxel or doxorubicin are cross-resistant to many other drugs and that, for these cell lines, ABCB1 over-expression is not necessary to confer resistance to either ET-743 or PM00104. Diversity of cross-resistance observed in these multi-drug resistant cell lines are associated with the initial drug used for in vitro selection, but not to ABCB1 expression. This study suggests that a common molecular pathway other than ABCB1 may be involved in the mechanism of resistance to ET-743 or PM00104.
ET-743（曲贝替定，Yondelis）和PM00104（Zalypsis）是具有抗肿瘤活性的海洋来源化合物。本研究旨在阐明ABCB1/MDR1和ABCC1/MRP1的表达与对ET-743或PM00104耐药性之间的关系。
我们评估了Pgp1、MRP1和BCRP蛋白的表达与ET-743或PM00104耐药性之间的关联，这些评估是在一组大量的多药耐药细胞系中进行的，这些细胞系来源于组织学上不相关的人类肿瘤，并用紫杉醇、阿霉素、顺铂、米托蒽醌或吉西他滨进行筛选。
用紫杉醇筛选出的耐药细胞系表达高水平的ABCB1（但不表达ABCC1或ABCG2/BCRP），对ET-743或PM00104均无交叉耐药性。相比之下，用阿霉素筛选出的耐药细胞系也表达高水平的ABCB1（但不表达ABCC1或ABCG2），但对ET-743和PM00104均有显著的交叉耐药性。用紫杉醇筛选出的细胞系对阿霉素、长春新碱和米托蒽醌有交叉耐药性，而上述大多数用阿霉素筛选出的细胞系对紫杉醇和长春新碱有交叉耐药性，但对米托蒽醌没有。相反，用顺铂和吉西他滨筛选出的细胞系对紫杉醇、阿霉素、ET-743或PM00104均无交叉耐药性。在阿霉素筛选出的细胞系中，通过小干扰RNA下调ABCB1的表达，可使细胞对阿霉素和紫杉醇部分敏感，但对ET-743或PM00104不敏感。
这些结果表明，对紫杉醇或阿霉素耐药的细胞系对许多其他药物有交叉耐药性，并且对于这些细胞系，ABCB
