Chloroquine-Mediated Lysosomal Dysfunction Enhances the Anticancer Effect of Nutrient Deprivation

Harhaji-Trajković, Ljubica; Arsikin, Katarina; Kravić-Stevović, Tamara; Petricevic, Sasa; Tovilović, Gordana; Pantovic, Aleksandar; Zogović, Nevena; Ristić, Biljana; Janjetović, Kristina; Bumbaširević, Vladimir; Trajkovič, Vladimir

doi:10.1007/s11095-012-0753-1

Cited by 63 publications

(46 citation statements)

References 48 publications

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“…In fact, CLQ promotes autophagy-independent chemosensitization [40] and increases apoptosis in melanoma cells sensitized by nutrient deprivation [41]. The ability of CLQ to downregulate AMPK not mimicked by autophagy inhibitors or LC3b shRNA emphasizes such observations [42]. Together, the presented data show the ability of CLQ to modulate NO production and protect endothelial function, emerging evidence for the role of autophagy in vascular pathophysiology.…”

Section: Discussionmentioning

confidence: 57%

Inhibition of Autophagy by Chloroquine Stimulates Nitric Oxide Production and Protects Endothelial Function during Serum Deprivation

Pestana

Oishi²,

Salistre-Araújo³

et al. 2015

Cell Physiol Biochem

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Background/Aims: Autophagy plays a fundamental role in cell survival under stress conditions such as nutrient deprivation. Decreased nitric oxide (NO) production, which may contribute to vascular dysfunction, is one of the consequences of autophagy in endothelial cells. The antimalarial drug chloroquine (CLQ) inhibits autophagy by blocking autophagosome formation and has been proposed as adjuvant chemotherapy in other diseases. Methods: Autophagy was induced by serum deprivation in Human Umbilical Vascular Endothelial Cells (HUVEC) as demonstrated by formation of Acidic Vesicular Organelles (AVOs), conversion of Microtubule-associated protein 1 light chain (LC3), and Sequestosome-1 (SQTM1/p62) degradation. Using endothelium-dependent vasorelaxation assays, intracellular NO production in an ex vivo rat aortic ring model pre-constricted with phenylephrine was estimated along with DAF-2 DA cell membrane-permeable NO sensitive fluorescent dye. Results: The inhibition of autophagy by CLQ restored NO levels, protected against superoxide generation and preserved morphology as well as proliferation of HUVEC under serum deprivation. Interestingly, the incubation of rat aortic rings with CLQ resulted in endothelium-dependent relaxation mediated by the increase of NO. Conclusion: These findings emphasize the importance of autophagy in endothelial function and demonstrate the potential use of autophagy inhibitors to protect vascular function during nutrient deprivation.

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Section: Discussionmentioning

confidence: 57%

Inhibition of Autophagy by Chloroquine Stimulates Nitric Oxide Production and Protects Endothelial Function during Serum Deprivation

Pestana

Oishi²,

Salistre-Araújo³

et al. 2015

Cell Physiol Biochem

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“…Published data have indicated tubular cell apoptosis is due to an enhanced mitochondrial pathway, resulting possibly from increased oxidative stress [17,22]. Another study suggests that a combined treatment with chloroquine and CR might be useful in cancer therapy [33]. Moreover, fasting sensitizes a variety of tumors to chemo- and radiotherapy [34,35].…”

Section: Discussionmentioning

confidence: 99%

Beneficial Effects of Short-Term Calorie Restriction against Cisplatin-Induced Acute Renal Injury in Aged Rats

Ning

Cai

et al. 2014

Nephron Exp Nephrol

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Background: The therapeutic use of the antineoplastic drug cisplatin (DDP) in the elderly is limited by its nephrotoxic effects. The aim of this study was to examine the effect of short-term calorie restriction (CR) on DDP-induced nephrotoxicity in aged rats. Methods: A group of 25-month-old male Sprague-Dawley rats were divided into two groups: ad libitum (AL) and CR, which were fed 60% of the food consumed by AL rats for 8 weeks. The two groups were each further randomly divided into two subgroups: OAL control, OAL+DDP, OCR control, and OCR+DDP. A single dose of DDP (6 mg/kg) was injected intraperitoneally. Functional and structural changes of the kidneys were evaluated quantitatively by biochemical, histopathological, and morphometric analyses. Results: At the end of the 8 weeks, rats in the OCR group lost 14.8% more body mass than rats in the OAL group. Pretreatment with CR had several effects: (1) it reduced the levels of blood urea nitrogen and serum creatinine, (2) it reduced the magnitude of the renal tubular epithelial damage, and (3) it significantly reduced the incidence of activated caspase-3 and TUNEL-positive cells in kidneys injured by DDP. However, SIRT1 had the opposite trend after DDP application between the two groups. Conclusions: Short-term CR exhibits a renoprotective effect in experimental DDP-induced renal injury, the mechanism of which may involve CR antiapoptotic effects and promotion of SIRT1.

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“…Of them, chloroquine and its analog hydroxychloroquine are the only clinically relevant autophagy inhibitors that are widely used as anti-malarial and anti-rheumatoid agents. It has been reported that chloroquinemediated lysosomal dysfunction enhanced its anticancer effect [95] . A major concern with the use of hydroxychloroquine is that high micromolar concentrations, which are not consistently achieved in patients, are required to block autophagy in vitro.…”

Section: Lysosomal Lumen Alkalizersmentioning

confidence: 99%

Application and interpretation of current autophagy inhibitors and activators

et al. 2013

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Autophagy is the major intracellular degradation system, by which cytoplasmic materials are delivered to and degraded in the lysosome. As a quality control mechanism for cytoplasmic proteins and organelles, autophagy plays important roles in a variety of human diseases, including neurodegenerative diseases, cancer, cardiovascular disease, diabetes and infectious and inflammatory diseases. The discovery of ATG genes and the dissection of the signaling pathways involved in regulating autophagy have greatly enriched our knowledge on the occurrence and development of this lysosomal degradation pathway. In addition to its role in degradation, autophagy may also promote a type of programmed cell death that is different from apoptosis, termed type II programmed cell death. Owing to the dual roles of autophagy in cell death and the specificity of diseases, the exact mechanisms of autophagy in various diseases require more investigation. The application of autophagy inhibitors and activators will help us understand the regulation of autophagy in human diseases, and provide insight into the use of autophagy-targeted drugs. In this review, we summarize the latest research on autophagy inhibitors and activators and discuss the possibility of their application in human disease therapy.

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Chloroquine-Mediated Lysosomal Dysfunction Enhances the Anticancer Effect of Nutrient Deprivation

Abstract: Combined treatment with chloroquine and calorie restriction might be useful in cancer therapy.

Cited by 63 publications

References 48 publications

Inhibition of Autophagy by Chloroquine Stimulates Nitric Oxide Production and Protects Endothelial Function during Serum Deprivation

Inhibition of Autophagy by Chloroquine Stimulates Nitric Oxide Production and Protects Endothelial Function during Serum Deprivation

Beneficial Effects of Short-Term Calorie Restriction against Cisplatin-Induced Acute Renal Injury in Aged Rats

Application and interpretation of current autophagy inhibitors and activators

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