KRAS-mutation status dependent effect of zoledronic acid in human non-small cell cancer preclinical models

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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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.

Item Type: Article
Subjects: R Medicine / orvostudomány > RB Pathology / patológia, kórtan
R Medicine / orvostudomány > RC Internal medicine / belgyógyászat > RC0254 Neoplasms. Tumors. Oncology (including Cancer) / daganatok, tumorok, onkológia
Depositing User: Dr. István Kenessey
Date Deposited: 03 Oct 2016 14:18
Last Modified: 03 Oct 2016 14:18

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