title: A-770041 reverses paclitaxel and doxorubicin resistance in osteosarcoma cells.
abstract: BACKGROUND
  Reversing multidrug resistance (MDR) has been an important goal for clinical and investigational oncologists. In the last few decades, significant effort has been made to search for inhibitors to reverse MDR by targeting ATP-binding cassette (ABC) transporters (Pgp, MRP) directly, but these efforts have achieved little clinical success. Protein kinases play important roles in many aspects of tumor cell growth and survival. Combinations of kinase inhibitors and chemotherapeutics have been observed to overcome cancer drug resistance in certain circumstances.
  
  
  METHODS
  We screened a kinase specific inhibitor compound library in human osteosarcoma MDR cell lines to identify inhibitors that were capable of reversing chemoresistance to doxorubicin and paclitaxel.
  
  
  RESULTS
  We identified 18 small molecules that significantly increase chemotherapy drug-induced cell death in human osteosarcoma MDR cell lines U-2OSMR and KHOSR2. We identified A-770041 as one of the most effective MDR reversing agents when combined with doxorubicin or paclitaxel. A-770041 is a potent Src family kinase (Lck and Src) inhibitor. Western blot analysis revealed A-770041 inhibits both Src and Lck activation and expression. Inhibition of Src expression in U-2OSMR and KHOSR2 cell lines using lentiviral shRNA also resulted in increased doxorubicin and paclitaxel drug sensitivity. A-770041 increases the intracellular drug accumulation as demonstrated by calcein AM assay.
  
  
  CONCLUSIONS
  These results indicate that small molecule inhibitor A-770041 may function to reverse ABCB1/Pgp-mediated chemotherapy drug resistance. Combination of Src family kinase inhibitor with regular chemotherapy drug could be clinically effective in MDR osteosarcoma.
authors.affiliation: Center for Sarcoma and Connective Tissue Oncology, Massachusetts General Hospital, 100 Blossom St,, Jackson 1115, Boston 02114, MA, USA. zduan@mgh.harvard.edu.
authors.forename: Zhenfeng
authors.initials: Z
authors.lastname: Duan
authors.forename: Jianming
authors.initials: J
authors.lastname: Zhang
authors.forename: Shunan
authors.initials: S
authors.lastname: Ye
authors.forename: Jacson
authors.initials: J
authors.lastname: Shen
authors.forename: Edwin
authors.initials: E
authors.lastname: Choy
authors.forename: Gregory
authors.initials: G
authors.lastname: Cote
authors.forename: David
authors.initials: D
authors.lastname: Harmon
authors.forename: Henry
authors.initials: H
authors.lastname: Mankin
authors.forename: Yingqi
authors.initials: Y
authors.lastname: Hua
authors.forename: Yu
authors.initials: Y
authors.lastname: Zhang
authors.forename: Nathanael S
authors.initials: NS
authors.lastname: Gray
authors.forename: Francis J
authors.initials: FJ
authors.lastname: Hornicek
mesh_terms: D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology; D001859:Bone Neoplasms / Q000188:drug therapy*; D045744:Cell Line, Tumor; D004317:Doxorubicin / Q000494:pharmacology; D018432:Drug Resistance, Multiple / Q000187:drug effects*; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D004357:Drug Synergism; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D012516:Osteosarcoma / Q000188:drug therapy*; D017239:Paclitaxel / Q000494:pharmacology; D019151:Peptide Library; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D011720:Pyrazoles / Q000494:pharmacology*; D011743:Pyrimidines / Q000494:pharmacology*; D019061:src-Family Kinases / Q000378:metabolism
chemical_list: C505452:1-methyl-1H-indole-2-carboxylic acid (4-(1-(4-(4-acetylpiperazin-1-yl)cyclohexyl)-4-amino-1H-pyrazolo(3,4-d)pyrimidin-3-yl)-2-methoxyphenyl)amide; D019151:Peptide Library; D047428:Protein Kinase Inhibitors; D011720:Pyrazoles; D011743:Pyrimidines; D004317:Doxorubicin; D019061:src-Family Kinases; D017239:Paclitaxel