title: Oxidative stress plays an important role in zoledronic acid-induced autophagy.
abstract: 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.
authors: Institute for Heart Research, Slovak Academy of Sciences and Centre of Excellence of SAS, Bratislava, Slovakia. drvinothk@gmail.com.
authors: V K M
authors: VK
authors: Khandelwal
authors: L M
authors: LM
authors: Mitrofan
authors: J M T
authors: JM
authors: Hyttinen
authors: K R
authors: KR
authors: Chaudhari
authors: R
authors: R
authors: Buccione
authors: K
authors: K
authors: Kaarniranta
authors: T
authors: T
authors: Ravingerová
authors: J
authors: J
authors: Mönkkönen
mesh_terms: D001343:Autophagy / Q000187:drug effects*; D050071:Bone Density Conservation Agents / Q000494:pharmacology / Q000627:therapeutic use*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D004164:Diphosphonates / Q000494:pharmacology / Q000627:therapeutic use*; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology / Q000627:therapeutic use*; D061986:MCF-7 Cells; D008798:Mevalonic Acid / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects*; D000077211:Zoledronic Acid
chemical_list: D050071:Bone Density Conservation Agents; D004164:Diphosphonates; D007093:Imidazoles; D000077211:Zoledronic Acid; D008798:Mevalonic Acid