KRAS-mutation status dependent effect of zoledronic acid in human non-small cell cancer preclinical models
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Tartalom: http://real.mtak.hu/41012/
Archívum: MTA Könyvtár
Gyűjtemény: Status = In Press


Type = Article
Cím:
KRAS-mutation status dependent effect of zoledronic acid in human non-small cell cancer preclinical models
Létrehozó:
Kenessey, István
KĂłi, Krisztina
Horváth, Orsolya
Cserepes, Mihály
Molnár, Dávid
Izsák, Vera
Dobos, Judit
Hegedűs, Balázs
Tímár, József
Tóvári, József
Kiadó:
Impact Journals
Dátum:
2016-09-26
Téma:
RB Pathology / patolĂłgia, kĂłrtan
RC0254 Neoplasms. Tumors. Oncology (including Cancer) / daganatok, tumorok, onkolĂłgia
Tartalmi leírás:
Background: 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.
Material and methods: 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.
Results: 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.
Conclusions: 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.
Nyelv:
magyar
Típus:
Article
PeerReviewed
info:eu-repo/semantics/article
Formátum:
text
Azonosító:
Kenessey, István and Kói, Krisztina and Horváth, Orsolya and Cserepes, Mihály and Molnár, Dávid and Izsák, Vera and Dobos, Judit and Hegedűs, Balázs and Tímár, József and Tóvári, József (2016) KRAS-mutation status dependent effect of zoledronic acid in human non-small cell cancer preclinical models. Oncotarget. ISSN 1949-2553 (In Press)
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