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Broad-spectrum modulation of ATP-binding cassette transport proteins by the taxane derivatives ortataxel (IDN-5109, BAY 59-8862) and tRA96023

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Abstract

Purpose

The taxanes paclitaxel and docetaxel are substrates for P-glycoprotein (Pgp), an ATP-binding cassette (ABC) transport protein associated with multidrug resistance (MDR). In contrast, the synthetic taxane ortataxel (BAY 59-8862, IDN-5109) is effective against Pgp-expressing cells by virtue of modulation of Pgp-mediated transport. The synthetic taxane tRA96023 also modulates Pgp and is noncytotoxic due to removal of the tubulin-binding side chain at the C-13 position of the taxane backbone. We studied the effects of ortataxel and tRA96023 on the other MDR-associated ABC transport proteins, multidrug resistance protein (MRP-1) and breast cancer resistance protein (BCRP, MXR, ABCG2).

Methods

Modulation of mitoxantrone, daunorubicin and doxorubicin retention and cytotoxicity by ortataxel and tRA96023 was studied in established cell lines overexpressing Pgp, MRP-1 and wild type (BCRPR482) and mutant (BCRPR482T) BCRP, and was compared with modulation by the established Pgp-, MRP-1- and BCRP-specific modulators PSC-833, probenecid and fumitremorgin C, respectively.

Results

Ortataxel effectively modulated drug retention and cytotoxicity in cell lines overexpressing MRP-1 and BCRPR482, in addition to Pgp. tRA96023 modulated drug retention and cytotoxicity in cell lines overexpressing BCRPR482 and Pgp, but not those overexpressing MRP-1. Neither ortataxel nor tRA96023 modulated BCRPR482T.

Conclusions

The synthetic taxane derivatives ortataxel and tRA96023 are broad-spectrum ABC protein modulators. Further studies will seek to identify a noncytotoxic synthetic taxane that modulates Pgp, MRP-1 and BCRP.

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Authors and Affiliations

  1. Leukemia Section, Department of Medicine, Roswell Park Cancer Institute, Elm and Carlton Streets, Buffalo, New York, 14263, USA

    Hans Minderman, Kieran L. O’Loughlin & Maria R. Baer

  2. Department of Pharmacology and Therapeutics, Roswell Park Cancer Institute, Elm and Carlton Streets, Buffalo, New York, 14263, USA

    Tracy A. Brooks, Ralph J. Bernacki & Maria R. Baer

  3. Department of Chemistry, State University of New York at Stony Brook, Stony Brook, New York, 11794-3400, USA

    Iwao Ojima

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  1. Hans Minderman
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  2. Tracy A. Brooks
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  3. Kieran L. O’Loughlin
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  4. Iwao Ojima
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  5. Ralph J. Bernacki
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  6. Maria R. Baer
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Corresponding author

Correspondence to Maria R. Baer.

Additional information

This work was supported by grants R21 CA098457 and R21 CA89938 (to M.R.B.), R01 CA73872 (to R.J.B.) and T32 CA09072-27 from the National Cancer Institute and R01 GM42798 from the National Institute of General Medical Sciences (to I.O.), by a Leukemia and Lymphoma Society Translational Research Program grant (to M.R.B.), by shared resources of the Roswell Park Cancer Center Support Grant (P30 CA16056) and by the Leonard S. LoVullo Memorial Fund for Leukemia Research and the Dennis J. Szefel, Jr Endowed Fund for Leukemia Research at Roswell Park Cancer Institute.

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Minderman, H., Brooks, T.A., O’Loughlin, K.L. et al. Broad-spectrum modulation of ATP-binding cassette transport proteins by the taxane derivatives ortataxel (IDN-5109, BAY 59-8862) and tRA96023. Cancer Chemother Pharmacol 53, 363–369 (2004). https://doi.org/10.1007/s00280-003-0745-2

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