<scp>CQ</scp> sensitizes human pancreatic cancer cells to gemcitabine through the lysosomal apoptotic pathway via reactive oxygen species

Fu, Zhiping; Cheng, Xi; Kuang, Jie; Feng, Haoran; Chen, Lingxie; Liang, Juyong; Shen, Xiaonan; Yuen, Stanley; Peng, Chenghong; Shen, Baiyong; Jin, Zhijian; Qiu, Weihua

doi:10.1002/1878-0261.12179

Cited by 33 publications

(30 citation statements)

References 38 publications

(37 reference statements)

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“…They are believed to inhibit lysosome-dependent autophagy and improve chemo and radio sensitivity [76]. Some of the most recent publications on this matter included breast cancer [77], pancreatic cancer [78,79], lung cancer [80], colon cancer [81], and bladder cancer [82].…”

Section: Quinolines: Chloroquine and Quinidinementioning

confidence: 99%

In Search of a Breakthrough Therapy for Glioblastoma Multiforme

Vasilev

Sofi

et al. 2018

Neuroglia

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Glioblastoma multiforme (GBM) is an extremely malignant type of brain cancer which originates from astrocytes or their precursors. Glioblastoma multiforme cells share some features with astrocytes but are characterized by highly unstable genomes with multiple driver mutations and aberrations. Effective therapies for GBM are lacking and hardly any progress has been made in the last 15 years in terms of improving the outcomes for patients. The lack of new especially targeted anti-GBM medications has prompted scientists in academia around the world to test whether any of the currently approved drugs might be used to fight this devastating disease. This approach is known as repurposing. Dozens of drugs have been reported to have anti-GBM properties in vitro but there is no solid evidence for the clinical efficacy of any of them. Perhaps the most interesting group of those repurposed are tricyclic antidepressants but the mechanism of their action on GBM cells remains obscure. In this brief review we consider various approaches to repurpose drugs for therapy of GBM and highlight their limitations. We also pay special attention to the mitochondria, which appear to be intimately involved in the process of apoptosis and could be a focus of future developments in search of a better treatment for patients suffering from GBM.

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Section: Quinolines: Chloroquine and Quinidinementioning

confidence: 99%

In Search of a Breakthrough Therapy for Glioblastoma Multiforme

Vasilev

Sofi

et al. 2018

Neuroglia

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“…Inhibition of these pathways suppresses PDAC tumor growth and prolongs survival in animal models (4,6,8). Additionally, engaging autophagic programs confers resistance to chemoradiation in PDAC cells (9)(10)(11), and high levels of autophagy markers are correlated with worse survival in resected PDAC patients (12).…”

mentioning

confidence: 99%

Lysosome inhibition sensitizes pancreatic cancer to replication stress by aspartate depletion

Elliott

Dann

et al. 2019

Proc. Natl. Acad. Sci. U.S.A.

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Functional lysosomes mediate autophagy and macropinocytosis for nutrient acquisition. Pancreatic ductal adenocarcinoma (PDAC) tumors exhibit high basal lysosomal activity, and inhibition of lysosome function suppresses PDAC cell proliferation and tumor growth. However, the codependencies induced by lysosomal inhibition in PDAC have not been systematically explored. We performed a comprehensive pharmacological inhibition screen of the protein kinome and found that replication stress response (RSR) inhibitors were synthetically lethal with chloroquine (CQ) in PDAC cells. CQ treatment reduced de novo nucleotide biosynthesis and induced replication stress. We found that CQ treatment caused mitochondrial dysfunction and depletion of aspartate, an essential precursor for de novo nucleotide synthesis, as an underlying mechanism. Supplementation with aspartate partially rescued the phenotypes induced by CQ. The synergy of CQ and the RSR inhibitor VE-822 was comprehensively validated in both 2D and 3D cultures of PDAC cell lines, a heterotypic spheroid culture with cancerassociated fibroblasts, and in vivo xenograft and syngeneic PDAC mouse models. These results indicate a codependency on functional lysosomes and RSR in PDAC and support the translational potential of the combination of CQ and RSR inhibitors. lysosome | autophagy | replication stress | pancreatic cancer | nucleotide metabolism P ancreatic ductal adenocarcinoma (PDAC) is the fourth leading cause of cancer-related death in the United States, and its incidence is increasing (1). PDAC carries a 5-y survival of less than 10%, as it is often diagnosed at a late stage and is widely refractory to available therapies. This lack of effective treatment options suggests an incomplete understanding of the biologic complexity of PDAC and mechanisms of therapeutic resistance.PDAC tumors are hypoperfused, resulting in poor nutrient delivery (2). To exist in this hostile microenvironment, PDAC cells rely on intracellular and extracellular scavenging pathways to acquire metabolic substrates for growth. Autophagy, a selfdegradative mechanism employed to recycle damaged cytosolic proteins and organelles, and macropinocytosis, the process of uptaking bulk extracellular material, are up-regulated in PDAC (3-6). As the final step of both autophagy and macropinocytosis, autophagic and endocytic cargo fuse with the lysosome, where macromolecules are degraded and substrates for metabolism are released (3, 4, 7). Inhibition of these pathways suppresses PDAC tumor growth and prolongs survival in animal models (4, 6, 8). Additionally, engaging autophagic programs confers resistance to chemoradiation in PDAC cells (9-11), and high levels of autophagy markers are correlated with worse survival in resected PDAC patients (12).The study of lysosomal function often focuses on proteolysis, which degrades misfolded proteins and damaged organelles (13,14). However, lysosomal degradation pathways also play a critical role in lipid (15-17) and nucleic acid metabolism. The recycling of nucleic ac...

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“…Then, flow cytometry was used to identify Annexin V-FITC/PI stained apoptotic cells. Annexin V + PI − cells were considered as early apoptotic and Annexin V + PI + cells were considered as late apoptotic ( 28 ). The results indicated that high concentration (20 mM) of HPβCD treatment increased the proportion of apoptotic cells compared with control and 2 mM HPβCD-treated groups ( Fig.…”

Section: Resultsmentioning

confidence: 99%

“…Cells in 6-replicated wells were treated with 8 µl CCK-8 and incubated at 37°C for 2 h. Absorbance was measured at a wavelength of 450 nm using a microtiter plate reader (Tecan Safire 2; Tecan Group, Ltd.). The specific formula used to calculate cell viability was described previously ( 28 ).…”

Section: Methodsmentioning

confidence: 99%

2‑Hydroxypropyl‑β‑cyclodextrin blocks autophagy flux and triggers caspase‑8‑mediated apoptotic cascades in HepG2 cells

Sun

Zong

2020

Mol Med Rep

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The cyclodextrin derivative, 2-Hydroxypropyl-β-cyclodextrin (HPβCD), from the cyclodextrin family is widely used as a drug carrier and offers promising strategies for treating neurodegenerative diseases and atherosclerosis regression. However, its side effects are not fully understood. Therefore, the aim of the present study was to investigate the possible adverse effects of relatively high concentrations of HPβCD on hepatocytes. It was found that a high dose (20 mM) of HPβCD treatment significantly inhibited the AKT/mTOR pathway and disrupted infusion of autophagosomes and lysosomes, which rapidly led to massive autophagosome accumulation in HepG2 cells. The autophagosomal membrane serves as a platform for caspase-8 oligomerization, which is considered as the key step for its self-activation. Using flow cytometry and TUNEL assay, increased apoptosis of HepG2 cells treated with a high dose HPβCD (20 mM) for 48 h was observed. In addition, western blotting results demonstrated that the expression of cleaved-caspase-8 was positively associated with microtubule-associated protein 1 light chain 3 BII expression, which is an indicator of autophagosome level in the cytoplasm. Therefore, the present study provided novel evidence that HPβCD might be a potential risk contributing to the pathophysiological process of hepatic diseases, especially in an autophagy-deficient state.

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CQ sensitizes human pancreatic cancer cells to gemcitabine through the lysosomal apoptotic pathway via reactive oxygen species

Cited by 33 publications

References 38 publications

In Search of a Breakthrough Therapy for Glioblastoma Multiforme

In Search of a Breakthrough Therapy for Glioblastoma Multiforme

Lysosome inhibition sensitizes pancreatic cancer to replication stress by aspartate depletion

2‑Hydroxypropyl‑β‑cyclodextrin blocks autophagy flux and triggers caspase‑8‑mediated apoptotic cascades in HepG2 cells

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