title: NVP-TAE684 reverses multidrug resistance (MDR) in human osteosarcoma by inhibiting P-glycoprotein (PGP1) function.
abstract: OBJECTIVE
  Increased expression of P-glycoprotein (PGP1) is one of the major causes of multidrug resistance (MDR) in cancer, including in osteosarcoma, which eventually leads to the failure of cancer chemotherapy. Thus, there is an urgent need to develop effective therapeutic strategies to override the expression and function of PGP1 to counter MDR in cancer patients.
  
  
  METHODS
  In an effort to search for new chemical entities targeting PGP1-associated MDR in osteosarcoma, we screened a 500+ compound library of known kinase inhibitors with established kinase selectivity profiles. We aimed to discover potential drug synergistic effects among kinase inhibitors and general chemotherapeutics by combining inhibitors with chemotherapy drugs such as doxorubicin and paclitaxel. The human osteosarcoma MDR cell lines U2OSR2 and KHOSR2 were used for the initial screen and secondary mechanistic studies.
  
  
  RESULTS
  After screening 500+ kinase inhibitors, we identified NVP-TAE684 as the most effective MDR reversing agent. NVP-TAE684 significantly reversed chemoresistance when used in combination with doxorubicin, paclitaxel, docetaxel, vincristine, ET-743 or mitoxantrone. NVP-TAE684 itself is not a PGP1 substrate competitive inhibitor, but it can increase the intracellular accumulation of PGP1 substrates in PGP1-overexpressing cell lines. NVP-TAE684 was found to inhibit the function of PGP1 by stimulating PGP1 ATPase activity, a phenomenon reported for other PGP1 inhibitors.
  
  
  CONCLUSIONS
  The application of NVP-TAE684 to restore sensitivity of osteosarcoma MDR cells to the cytotoxic effects of chemotherapeutics will be useful for further study of PGP1-mediated MDR in human cancer and may ultimately benefit cancer patients.
authors.affiliation: Center for Sarcoma and Connective Tissue Oncology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
authors.forename: Shunan
authors.initials: S
authors.lastname: Ye
authors.affiliation: Cutaneous Biology Research Center, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
authors.forename: Jianming
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Center for Sarcoma and Connective Tissue Oncology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
authors.forename: Jacson
authors.initials: J
authors.lastname: Shen
authors.affiliation: Center for Sarcoma and Connective Tissue Oncology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
authors.forename: Yan
authors.initials: Y
authors.lastname: Gao
authors.affiliation: Cutaneous Biology Research Center, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
authors.forename: Ying
authors.initials: Y
authors.lastname: Li
authors.affiliation: Center for Sarcoma and Connective Tissue Oncology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
authors.forename: Edwin
authors.initials: E
authors.lastname: Choy
authors.affiliation: Center for Sarcoma and Connective Tissue Oncology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
authors.forename: Gregory
authors.initials: G
authors.lastname: Cote
authors.affiliation: Center for Sarcoma and Connective Tissue Oncology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
authors.forename: David
authors.initials: D
authors.lastname: Harmon
authors.affiliation: Center for Sarcoma and Connective Tissue Oncology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
authors.forename: Henry
authors.initials: H
authors.lastname: Mankin
authors.affiliation: Dana Farber Cancer Institute, Harvard Medical School, Boston, MA, USA.
authors.forename: Nathanael S
authors.initials: NS
authors.lastname: Gray
authors.affiliation: Center for Sarcoma and Connective Tissue Oncology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
authors.forename: Francis J
authors.initials: FJ
authors.lastname: Hornicek
authors.affiliation: Center for Sarcoma and Connective Tissue Oncology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
authors.forename: Zhenfeng
authors.initials: Z
authors.lastname: Duan
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B / Q000037:antagonists & inhibitors*; D000970:Antineoplastic Agents / Q000494:pharmacology; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D004317:Doxorubicin / Q000494:pharmacology; D018432:Drug Resistance, Multiple / Q000187:drug effects*; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D006801:Humans; D012516:Osteosarcoma / Q000378:metabolism; D017239:Paclitaxel / Q000494:pharmacology; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D011743:Pyrimidines / Q000494:pharmacology*; D000097202:ATP-Binding Cassette Sub-Family B Member 4
chemical_list: D018435:ATP Binding Cassette Transporter, Subfamily B; D000970:Antineoplastic Agents; D004317:Doxorubicin; D017239:Paclitaxel; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D000097202:ATP-Binding Cassette Sub-Family B Member 4; C516714:NVP-TAE684