title: Increased cellular accumulation and distribution of amrubicin contribute to its activity in anthracycline-resistant cancer cells.
abstract: OBJECTIVE
  Multi-drug resistance and cumulative cardiotoxicity are major limitations for the clinical use of anthracyclines. Here, we evaluated and compared the cross-resistance of amrubicin, a third-generation synthetic anthracycline and potent topoisomerase (topo)-II inhibitor with little or no observed cardiotoxicity to other anthracyclines and the topo-II inhibitor etoposide in drug-resistant tumor models in order to elucidate its potential mechanisms of action.
  
  
  METHODS
  Amrubicin activity was assessed in multi-drug-resistant cell lines and human tumor explants using cytotoxicity assays, confocal microscopy, fluorescence time-lapse imaging, flow cytometry, immunoblotting, and gene expression profiling techniques.
  
  
  RESULTS
  We demonstrate that both doxorubicin-resistant tumor cell lines and several drug-resistant human ovarian and breast tumor explants retain sensitivity to amrubicin. In addition, we observed similar levels of amrubicin uptake and accumulation in doxorubicin-sensitive versus doxorubicin-resistant cell lines. Although amrubicin is a weak P-glycoprotein substrate, transport and retention of amrubicin were not solely modulated by P-glycoprotein in the resistant cell lines overexpressing drug efflux pumps. The cellular retention of amrubicin is likely to be a result of rapid influx due to its high intrinsic permeability and lipophilic properties, and this may explain why amrubicin overcomes pleiotropic drug resistance. Consistent with drug accumulation studies, amrubicin induced DNA damage, G(2)-M cell cycle arrest, and apoptosis in both doxorubicin-sensitive and doxorubicin-resistant lines. Using gene expression profiling studies, several classes of genes were significantly and uniquely regulated following amrubicin, but not doxorubicin or etoposide, treatment.
  
  
  CONCLUSIONS
  Amrubicin appears to have a distinct mode of action that overcomes typical anthracycline resistance mechanisms. Therefore, amrubicin may be useful in the treatment of anthracycline-refractory or anthracycline-resistant tumors.
authors: Translational Development Department, Celgene Corporation, 1500 Owens St Suite 600, San Francisco, CA 94158, USA.
authors: Vidya
authors: V
authors: Mamidipudi
authors: Tao
authors: T
authors: Shi
authors: Helen
authors: H
authors: Brady
authors: Sekhar
authors: S
authors: Surapaneni
authors: Rajesh
authors: R
authors: Chopra
authors: Sharon L
authors: SL
authors: Aukerman
authors: Carla
authors: C
authors: Heise
authors: Victoria
authors: V
authors: Sung
mesh_terms: D018943:Anthracyclines / Q000493:pharmacokinetics* / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000493:pharmacokinetics* / Q000494:pharmacology*; D001943:Breast Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism; D053148:Caspase 3 / Q000378:metabolism; D048708:Cell Growth Processes / Q000187:drug effects; D045744:Cell Line, Tumor; D004249:DNA Damage; D004317:Doxorubicin / Q000493:pharmacokinetics / Q000494:pharmacology; D019008:Drug Resistance, Neoplasm; D015251:Epirubicin / Q000494:pharmacology; D005260:Female; D059565:G2 Phase Cell Cycle Checkpoints / Q000187:drug effects; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D059566:M Phase Cell Cycle Checkpoints / Q000187:drug effects; D010051:Ovarian Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism; D059005:Topoisomerase II Inhibitors / Q000493:pharmacokinetics / Q000494:pharmacology; D014594:Uterine Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism
chemical_list: D018943:Anthracyclines; D000970:Antineoplastic Agents; D059005:Topoisomerase II Inhibitors; D015251:Epirubicin; D004317:Doxorubicin; C055866:amrubicin; D053148:Caspase 3