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The Basis of Anthracycline Drugs Transport by P‐Glycoprotein
Author(s) -
Nguyen Phuong H.,
Sigdel Krishna P.,
Kings Gavin M.,
Roberts Arthur G.
Publication year - 2019
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.2019.33.1_supplement.507.3
Subject(s) - daunorubicin , p glycoprotein , doxorubicin , anthracycline , transporter , efflux , pharmacology , chemistry , biochemistry , atp hydrolysis , cancer cell , tryptophan , atp binding cassette transporter , multiple drug resistance , biology , cancer , medicine , enzyme , chemotherapy , leukemia , immunology , atpase , amino acid , breast cancer , gene , antibiotics
P‐glycoprotein (Pgp) is an ATP‐dependent efflux transporter and plays a major role in anti‐cancer drug resistance by pumping a chemically diverse range of cytotoxic drugs from cancerous tumors. Despite numerous studies with the transporter, the molecular features that drive anti‐cancer drug efflux are not well understood. Even subtle differences in the anti‐cancer drug molecular structure can lead to dramatic differences in their transport rates. To unmask these structural differences, the focus of this study was on the closely‐related anthracycline drugs daunorubicin and doxorubicin. While only differing in the positions of their hydroxyl functional groups, daunorubicin has a 5‐fold higher transport rate than doxorubicin. They were both anticipated to activate Pgp‐mediated ATP hydrolysis, but instead they reduced Pgp‐mediated ATP hydrolysis below basal levels and to the same extent. This suggested that daunorubicin and doxorubicin mediated ATP hydrolysis of Pgp similarly. The KD values measured from from intrinsic tryptophan fluorescence of the transporter for both daunorubicin and doxorubicin are insignificantly different, implying that two drugs have similar affinity for the transporter. Interestingly, acrylamide quenching of Pgp tryptophan fluorescence revealed that daunorubicin had larger effects on the transporter conformation than doxorubicin. These changes are consistent with shifts in the punctate features of atomic force microscopy (AFM) images of Pgp in the absence and presence of the drugs. This information was used to develop a conformationally‐gated model for anthracycline transport by Pgp. Support or Funding Information NIH 1RO1CA204846‐01A1 This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal .