Diverse cross-resistance phenotype to ET-743 and PM00104 in multi-drug resistant cell lines.
OBJECTIVE
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.


METHODS
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.


RESULTS
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.


CONCLUSIONS
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.
Duan
Zhenfeng
Z
Sarcoma Biology Laboratory, Center for Sarcoma and Connective Tissue Oncology, Massachusetts General Hospital, 100 Blossom St. Jackson 1106, Boston, MA 02114, USA. zduan@partners.org
Choy
Edwin
E
Jimeno
Jose Maria
JM
Cuevas
Carmen Del Maria
Cdel M
Mankin
Henry J
HJ
Hornicek
Francis J
FJ
D018435:ATP Binding Cassette Transporter, Subfamily B / Q000096:biosynthesis; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters / Q000096:biosynthesis; D000970:Antineoplastic Agents / Q000494:pharmacology*; D015153:Blotting, Western; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D004149:Dioxoles / Q000494:pharmacology*; D018432:Drug Resistance, Multiple / Q000187:drug effects*; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D006801:Humans; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000096:biosynthesis; D009363:Neoplasm Proteins / Q000096:biosynthesis; D044005:Tetrahydroisoquinolines / Q000494:pharmacology*; D000077606:Trabectedin; D000097202:ATP-Binding Cassette Sub-Family B Member 4
D018435:ATP Binding Cassette Transporter, Subfamily B; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters; D000970:Antineoplastic Agents; D004149:Dioxoles; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D009363:Neoplasm Proteins; D044005:Tetrahydroisoquinolines; D000077606:Trabectedin; D000097202:ATP-Binding Cassette Sub-Family B Member 4; C116614:ABCG2 protein, human; C500383:PM 00104; C421109:multidrug resistance-associated protein 1