title: KRAS-mutation status dependent effect of zoledronic acid in human non-small cell cancer preclinical models.
abstract: In non-small cell lung cancer (NSCLC) KRAS-mutant status is a negative prognostic and predictive factor. Nitrogen-containing bisphosphonates inhibit prenylation of small G-proteins (e.g. Ras, Rac, Rho) and thus may affect proliferation and migration. In our preclinical work, we investigated the effect of an aminobisphosphonate compound (zoledronic acid) on mutant and wild type KRAS-expressing human NSCLC cell lines.
  
  
  
  We confirmed that zoledronic acid was unable to inhibit the prenylation of mutant K-Ras unlike in the case of wild type K-Ras. In case of in vitro proliferation, the KRAS-mutant human NSCLC cell lines showed resistance to zoledronic acid wild-type KRAS-cells proved to be sensitive. Combinatory application of zoledronic acid enhanced the cytostatic effect of cisplatin. Zoledronic acid did not induce significant apoptosis. In xenograft model, zoledronic acid significantly reduced the weight of wild type KRAS-EGFR-expressing xenograft tumor by decreasing the proliferative capacity. Futhermore, zoledronic acid induced VEGF expression and improved in vivo tumor vascularization.
  
  
  
  Membrane association of K-Ras was examined by Western-blot. In vitro cell viability, apoptotic cell death and migration were measured in NSCLC lines with different molecular background. The in vivo effect of zoledronic acid was investigated in a SCID mouse subcutaneous xenograft model.
  
  
  
  The in vitro and in vivo inhibitory effect of zoledronic acid was based on the blockade of cell cycle in wild type KRAS-expressing human NSCLC cells. The zoledronic acid induced vascularization supported in vivo cytostatic effect. Our preclinical investigation suggests that patients with wild type KRAS-expressing NSCLC could potentially benefit from aminobisphosphonate therapy.
authors: 2nd Department of Pathology, Semmelweis University, Budapest, Hungary.|National Cancer Registry, National Institute of Oncology, Budapest, Hungary.
authors: István
authors: I
authors: Kenessey
authors: 2nd Department of Pathology, Semmelweis University, Budapest, Hungary.
authors: Krisztina
authors: K
authors: Kói
authors: Department of Experimental Pharmacology, National Institute of Oncology, Budapest, Hungary.
authors: Orsolya
authors: O
authors: Horváth
authors: Department of Experimental Pharmacology, National Institute of Oncology, Budapest, Hungary.|Institute of Enzymology, Research Centre for Natural Sciences, Hungarian Academy of Sciences, Budapest, Hungary.
authors: Mihály
authors: M
authors: Cserepes
authors: 2nd Department of Pathology, Semmelweis University, Budapest, Hungary.
authors: Dávid
authors: D
authors: Molnár
authors: 2nd Department of Pathology, Semmelweis University, Budapest, Hungary.
authors: Vera
authors: V
authors: Izsák
authors: Vichem Chemie Ltd., Budapest, Hungary.
authors: Judit
authors: J
authors: Dobos
authors: Hungarian Academy of Sciences-Semmelweis University Molecular Oncology Research Group, Budapest, Hungary.
authors: Balázs
authors: B
authors: Hegedűs
authors: Department of Experimental Pharmacology, National Institute of Oncology, Budapest, Hungary.
authors: József
authors: J
authors: Tóvári
authors: 2nd Department of Pathology, Semmelweis University, Budapest, Hungary.|Hungarian Academy of Sciences-Semmelweis University Molecular Oncology Research Group, Budapest, Hungary.
authors: József
authors: J
authors: Tímár
mesh_terms: D000072283:A549 Cells; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D014408:Biomarkers, Tumor / Q000235:genetics*; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D002453:Cell Cycle / Q000187:drug effects; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002945:Cisplatin / Q000494:pharmacology; D004164:Diphosphonates / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D020022:Genetic Predisposition to Disease; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology*; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D008297:Male; D008807:Mice, Inbred BALB C; D016513:Mice, SCID; D009154:Mutation; D009361:Neoplasm Invasiveness; D009389:Neovascularization, Pathologic; D010641:Phenotype; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics*; D015398:Signal Transduction / Q000187:drug effects; D047368:Tumor Burden / Q000187:drug effects; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays; D000077211:Zoledronic Acid
chemical_list: D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor; D004164:Diphosphonates; D007093:Imidazoles; C117307:KRAS protein, human; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; D000077211:Zoledronic Acid; D016283:Proto-Oncogene Proteins p21(ras); D002945:Cisplatin
keywords: human non-small cell lung cancer; ras inhibitor; xenograft model; zoledronic acid