Chloroquine-mediated lysosomal dysfunction enhances the anticancer effect of nutrient deprivation.
2012
Аутори:
Harhaji-Trajković, LjubicaArsikin, Katarina
Kravić-Stevović, Tamara
Petricevic, Sasa
Tovilović-Kovačević, Gordana
Pantović, Aleksandar
Zogović, Nevena
Ristić, Biljana
Janjetović, Kristina
Bumbaširević, Vladimir
Trajković, Vladimir
Тип документа:
Чланак у часопису (Објављена верзија)
Метаподаци
Приказ свих података о документуАпстракт:
Purpose To investigate the ability of chloroquine, a lysosomotropic autophagy inhibitor, to enhance the anticancer effect of nutrient deprivation.
Methods Serum-deprived U251 glioma, B16 melanoma and L929 fibrosarcoma cells were treated with chloroquine in vitro. Cell viability was measured by crystal violet and MTT assay. Oxidative stress, apoptosis/necrosis and intracellular acidification were analyzed by flow cytometry. Cell morphology was examined by light and electron microscopy. Activation of AMP-activated protein kinase (AMPK) and autophagy were monitored by immunoblotting. RNA interference was used for AMPK and LC3b knockdown. The anticancer efficiency of intraperitoneal chloroquine in calorie restricted mice was assessed using a B16mouse melanoma model.
Results Chloroquine rapidly killed serum-starved cancer cells in vitro. This effect was not mimicked by autophagy inhibitors or LC3b shRNA, indicating autophagy-independent mechanism. Chloroquine-induced lysosomal accumulation and oxidative stress, leading tomitochondrial depolarization, caspase activation and mixed apoptotic/necrotic cell death, were prevented by lysosomal acidification inhibitor bafilomycin. AMPK downregulation participated in chloroquine action, as AMPK activation reduced, and AMPK shRNA
mimicked chloroquine toxicity. Chloroquine inhibited melanoma growth in calorie-restricted mice, causing lysosomal accumulation, mitochondrial disintegration and selective necrosis of tumor cells.
Conclusion Combined treatment with chloroquine and calorie restriction might be useful in cancer therapy.
Кључне речи:
AMPK; autophagy; caloric restriction; cancer; chloroquineИзвор:
Pharmaceutical Research, 2012, 29, 8, 2249-2263Финансирање / пројекти:
- Unesco L'Oreal za žene u nauci čiji je nosilac bila dr Harhaji-Trajkovic Ljubica broj ugovora 403F
- Улога аутофагије у регулацији смрти туморских ћелија (RS-MESTD-Basic Research (BR or ON)-173053)
- Модулација сигналних путева који контролишу интрацелуларни енергетски баланс у терапији тумора и неуро-имуно-ендокриних поремећаја (RS-MESTD-Integrated and Interdisciplinary Research (IIR or III)-41025)
DOI: 10.1007/s11095-012-0753-1
ISSN: 0724-8741
PubMed: 21871960