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

Cancer Chemother Pharmacol. 2009 May;63(6):1121-9. doi: 10.1007/s00280-008-0843-2. Epub 2008 Oct 1.

Abstract

Purpose: 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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • ATP Binding Cassette Transporter, Subfamily B / biosynthesis
  • ATP Binding Cassette Transporter, Subfamily G, Member 2
  • ATP-Binding Cassette Sub-Family B Member 4
  • ATP-Binding Cassette Transporters / biosynthesis
  • Antineoplastic Agents / pharmacology*
  • Blotting, Western
  • Cell Line, Tumor
  • Cell Survival / drug effects
  • Dioxoles / pharmacology*
  • Drug Resistance, Multiple / drug effects*
  • Drug Resistance, Neoplasm / drug effects*
  • Humans
  • Multidrug Resistance-Associated Proteins / biosynthesis
  • Neoplasm Proteins / biosynthesis
  • Tetrahydroisoquinolines / pharmacology*
  • Trabectedin

Substances

  • ABCG2 protein, human
  • ATP Binding Cassette Transporter, Subfamily B
  • ATP Binding Cassette Transporter, Subfamily G, Member 2
  • ATP-Binding Cassette Transporters
  • Antineoplastic Agents
  • Dioxoles
  • Multidrug Resistance-Associated Proteins
  • Neoplasm Proteins
  • PM 00104
  • Tetrahydroisoquinolines
  • Trabectedin
  • multidrug resistance-associated protein 1