Abstract
BackgroundIn 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.ResultsWe 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.Materials and methodsMembrane 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.ConclusionsThe 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.
Highlights
Lung cancer is the lead neoplastic cause of death, both incidence and mortality show constant elevation [1]
Zoledronic acid significantly reduced the weight of wild type KRAS-epidermal growth factor receptor (EGFR)-expressing xenograft tumor by decreasing the proliferative capacity
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 non-small cell lung cancer (NSCLC) cells
Summary
Lung cancer is the lead neoplastic cause of death, both incidence and mortality show constant elevation [1]. Treatment opportunities for non-small cell lung cancer (NSCLC) were very limited, traditionally the first option was surgical resection, where available, complementing cisplatin-based cytostatic therapy [3]. The situation has completely changed with the appearance of target www.impactjournals.com/oncotarget based therapy: small molecule EGFR-TKIs (e.g. gefitinib, erlotinib) have effects on cancer cells that carry the activating mutation of EGFR [4]. Mutant KRAS is a negative prognostic and predictive factor of both classic and target based therapy, links to poor survival and increased progression. According to the recent guidelines, before administration of EGFRTKI the mutational status of KRAS as well as EGFR is required to be examined [5]. In non-small cell lung cancer (NSCLC) KRAS-mutant status is a negative prognostic and predictive factor. We investigated the effect of an aminobisphosphonate compound (zoledronic acid) on mutant and wild type KRASexpressing human NSCLC cell lines
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