title: Combination treatment with doxorubicin and gamitrinib synergistically augments anticancer activity through enhanced activation of Bim.
abstract: BACKGROUND
  A common approach to cancer therapy in clinical practice is the combination of several drugs to boost the anticancer activity of available drugs while suppressing their unwanted side effects. In this regard, we examined the efficacy of combination treatment with the widely-used genotoxic drug doxorubicin and the mitochondriotoxic Hsp90 inhibitor gamitrinib to exploit disparate stress signaling pathways for cancer therapy.
  
  
  METHODS
  The cytotoxicity of the drugs as single agents or in combination against several cancer cell types was analyzed by MTT assay and the synergism of the drug combination was evaluated by calculating the combination index. To understand the molecular mechanism of the drug synergism, stress signaling pathways were analyzed after drug combination. Two xenograft models with breast and prostate cancer cells were used to evaluate anticancer activity of the drug combination in vivo. Cardiotoxicity was assessed by tissue histology and serum creatine phosphokinase concentration.
  
  
  RESULTS
  Gamitrinib sensitized various human cancer cells to doxorubicin treatment, and combination treatment with the two drugs synergistically increased apoptosis. The cytotoxicity of the drug combination involved activation and mitochondrial accumulation of the proapoptotic Bcl-2 family member Bim. Activation of Bim was associated with increased expression of the proapoptotic transcription factor C/EBP-homologous protein and enhanced activation of the stress kinase c-Jun N-terminal kinase. Combined drug treatment with doxorubicin and gamitrinib dramatically reduced in vivo tumor growth in prostate and breast xenograft models without increasing cardiotoxicity.
  
  
  CONCLUSIONS
  The drug combination showed synergistic anticancer activities toward various cancer cells without aggravating the cardiotoxic side effects of doxorubicin, suggesting that the full therapeutic potential of doxorubicin can be unleashed through combination with gamitrinib.
authors.forename: Hye-Kyung
authors.initials: HK
authors.lastname: Park
authors.forename: Ji-Eun
authors.initials: JE
authors.lastname: Lee
authors.forename: Jaehwa
authors.initials: J
authors.lastname: Lim
authors.forename: Da-Eun
authors.initials: DE
authors.lastname: Jo
authors.forename: Soo-Ah
authors.initials: SA
authors.lastname: Park
authors.forename: Pann-Ghill
authors.initials: PG
authors.lastname: Suh
authors.affiliation: Department of Biological Sciences, School of Life Sciences, UNIST, 50 UNIST St,, Ulsan 689-798, South Korea. kangbh@unist.ac.kr.
authors.forename: Byoung Heon
authors.initials: BH
authors.lastname: Kang
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D051017:Apoptosis Regulatory Proteins / Q000819:agonists* / Q000378:metabolism; D000072224:Bcl-2-Like Protein 11; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D004195:Disease Models, Animal; D004317:Doxorubicin / Q000008:administration & dosage / Q000494:pharmacology*; D004357:Drug Synergism; D006801:Humans; D008565:Membrane Proteins / Q000819:agonists* / Q000378:metabolism; D051379:Mice; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D009369:Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D011518:Proto-Oncogene Proteins / Q000819:agonists* / Q000378:metabolism; D051742:Transcription Factor CHOP / Q000819:agonists / Q000378:metabolism; D047368:Tumor Burden / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D051017:Apoptosis Regulatory Proteins; C000606775:BCL2L11 protein, human; D000072224:Bcl-2-Like Protein 11; C000606776:Bcl2l11 protein, mouse; C497249:DDIT3 protein, human; D008565:Membrane Proteins; D011518:Proto-Oncogene Proteins; D051742:Transcription Factor CHOP; D004317:Doxorubicin