Several pre-clinical and clinical studies have demonstrated zoledronic acid (Zol), which regulates the mevalonate pathway, has efficient anti-cancer effects. Zol can also induce autophagy. The aim of this study is to add new understanding to the mechanism of autophagy induction by Zol. LC3B-II, the marker for autophagy was increased by Zol treatment in breast cancer cells. Autophagosomes induced by Zol were visualized and quantified in both transient (pDendra2-hLC3) and stable MCF-7-GFP-LC3 cell lines. Acidic vesicular organelles were quantified using acridine orange. Zol induced a dose and time dependent autophagy. Treatment of Zol increased oxidative stress in MCF-7 cells, which was reversed by GGOH or anti-oxidants. On the other hand, treatment with GGOH or anti-oxidants resulted in decreased levels of LC3B-II. Further, the induced autophagy was irreversible, as the washout of Zol after 2 h or 24 h resulted in similar levels of autophagy, as induced by continuous treatment after 72 h. Thus, it can be summarized that Zol can induce a dose dependent but irreversible autophagy, by its effect on the mevalonate pathway and oxidative stress. This study adds to the understanding of the mechanism of action of Zol, and that it can induce autophagy at clinically relevant shorter exposure times in cancer cells.

Department of Ophthalmology Institute of Clinical Medicine University of Eastern Finland Kuopio Finland

Department of Ophthalmology Kuopio University Hospital Kuopio Finland

Department of Translational Pharmacology Consorzio Mario Negri Sud Santa Maria Imbaro Italy

INSERM U908 Signalisation des facteurs de croissance dans le cancer du sein Protéomique fonctionnelle Université des Sciences et Technologies de Lille 1 Villeneuve d'Ascq France

Institute for Heart Research Slovak Academy of Sciences and Centre of Excellence of SAS Bratislava Slovakia

School of Pharmacy University of Eastern Finland Kuopio Finland

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