Palladium nanoparticles induce autophagy and autophagic flux blockade in Hela cells

Zhang, Li; Chen, Xuerui; Wu, Jianzhou; Ding, Shiping; Wang, Xu; Lei, Qunfang; Fang, Wenjun

doi:10.1039/c7ra11400a

Cited by 18 publications

(9 citation statements)

References 50 publications

(49 reference statements)

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“…For example, the autophagy inhibitor, chloroquine, enhanced RMS cell death induced by ciclopirox olamine, bortezomib and 17-DMAG and stimulation of autophagy by rapamycin prevented this 54,55 . Consistent with our findings, palladium nanoparticles have recently been shown to block autophagic flux in Hela cells as shown by increased LC3II/I ratios, reduced degradation of p62 and autophagosome accumulation 56 . It is important to note that AJ-5 induces autophagy PCD in melanoma and breast cancer cells, which suggests that the effect of palladium complexes on autophagy may be cancer type specific.…”

Section: Discussionsupporting

confidence: 92%

The palladacycle complex AJ-5 induces apoptotic cell death while reducing autophagic flux in rhabdomyosarcoma cells

Bleloch

Toit

Gibhard

et al. 2019

Cell Death Discovery

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Rhabdomyosarcoma (RMS) forms in skeletal muscle and is the most common soft tissue sarcoma in children and adolescents. Current treatment is associated with debilitating side effects and treatment outcomes for patients with metastatic disease are dismal. Recently, a novel binuclear palladacycle, AJ-5, was shown to exert potent cytotoxicity in melanoma and breast cancer and to present with negligible adverse effects in mice. This study investigates the anti-cancer activity of AJ-5 in alveolar and embryonal RMS. IC50 values of ≤ 0.2 µM were determined for AJ-5 and it displayed a favourable selectivity index of >2. Clonogenic and migration assays showed that AJ-5 inhibited the ability of RMS cells to survive and migrate, respectively. Western blotting revealed that AJ-5 induced levels of key DNA damage response proteins (γH2AX, p-ATM and p-Chk2) and the p38/MAPK stress pathway. This correlated with an upregulation of p21 and a G1 cell cycle arrest. Annexin V-FITC/propidium iodide staining revealed that AJ-5 induced apoptosis and necrosis. Apoptosis was confirmed by the detection of cleaved PARP and increased levels and activity of cleaved caspases-3, -7, -8 and -9. Furthermore, AJ-5 reduced autophagic flux as shown by reduced LC3II accumulation in the presence of bafilomycin A1 and a significant reduction in autophagosome flux J. Finally, pharmacokinetic studies in mice show that AJ-5 has a promising half-life and that its volume of distribution is high, its clearance low and its intraperitoneal absorption is good. Together these findings suggest that AJ-5 may be an effective chemotherapeutic with a desirable mechanism of action for treating drug-resistant and advanced sarcomas.

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Section: Discussionsupporting

confidence: 92%

The palladacycle complex AJ-5 induces apoptotic cell death while reducing autophagic flux in rhabdomyosarcoma cells

Bleloch

Toit

Gibhard

et al. 2019

Cell Death Discovery

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“…214 Palladium NPs (PdNPs) affect autophagosome accumulation in two ways; at low concentrations, autophagy activation is through the mTOR signaling pathway, while at high concentrations, the autophagosome accumulation is dominated by the autophagic flux blockade resulting from lysosome impairment. 215 Similarly, silica NPs induce autophagy at noncytotoxic levels, while they block autophagic flux at high doses. 216 The size and charge of NPs is another important factor in modulating the induction of autophagy.…”

Section: ■ the Tumor Microenvironmentmentioning

confidence: 99%

Nanoparticle Interactions with the Tumor Microenvironment

et al. 2019

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Compared to normal tissues, the tumor microenvironment (TME) has a number of aberrant characteristics including hypoxia, acidosis, and vascular abnormalities. Many researchers have sought to exploit these anomalous features of the TME to develop anticancer therapies, and several nanoparticle-based cancer therapeutics have resulted. In this Review, we discuss the composition and pathophysiology of the TME, introduce nanoparticles (NPs) used in cancer therapy, and address the interaction between the TME and NPs. Finally, we outline both the potential problems that affect TME-based nanotherapy and potential strategies to overcome these challenges.

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“…Transcriptional activation of the lysosome–autophagy system in response to internalization of foreign materials may lead to enhancement of the cellular clearance capacity, resulting in an increase in the extent of degradation of intracellular constituents normally degraded by autophagy. − Autophagic clearance, however, depends on the cooperation of multiple processes that culminate in the formation of autolysosomes and degradation of cargo. Impairment of different factors of the lysosome–autophagy system, which has been reported in association with cellular internalization of some nano-sized materials, − typically results in blockage of autophagic flux and, possibly, accumulation of intracellular autophagic substrates. ,, Biopersistent nanomaterials, for instance, may induce transcriptional upregulation of the lysosome–autophagy system, but may also affect lysosomal integrity, disrupting the formation of autolysosomes and, ultimately, impairing clearance of autophagic cargo …”

Section: Introductionmentioning

confidence: 99%

“…Impairment of different factors of the lysosome−autophagy system, which has been reported in association with cellular internalization of some nano-sized materials, 26−28 typically results in blockage of autophagic flux and, possibly, accumulation of intracellular autophagic substrates. 19,21,29 Biopersistent nanomaterials, for instance, may induce transcriptional upregulation of the lysosome−autophagy system, but may also affect lysosomal integrity, disrupting the formation of autolysosomes and, ultimately, impairing clearance of autophagic cargo. 26 The autophagic response to engineered nanomaterials seems to vary dramatically depending on the material's physicochemical properties such as size 21 and surface charge.…”

Section: ■ Introductionmentioning

confidence: 99%

Zinc Oxide Particles Induce Activation of the Lysosome–Autophagy System

Popp

Segatori

2019

ACS Omega

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Metal-oxide-based materials are highly versatile and used in a wide variety of applications ranging from medical technology to personal care products. Generally recognized as safe by the US Food and Drug Administration, zinc oxide (ZnO) has been increasingly used in pharmaceutical, cosmetic, food, and commodity chemical industries. As a result, exposure to nano- and micron-sized ZnO particles through occupational processes and consumer products is increasing and has raised concerns over the health effects associated with the large-scale production and commercialization of ZnO-based materials. It is therefore important to investigate the interaction of ZnO particles with biological systems and elucidate the consequent effect on cell physiology. Of particular interest is the autophagic response to zinc oxide particles, as autophagy is the first line of defense activated in response to the uptake of foreign materials. As the main cellular catabolic pathway, the lysosome–autophagy system plays an important homeostatic function and defects or deficiency of this degradation system is associated with the cellular pathogenesis of a number of human diseases, ranging from neurodegenerative disorders to cancer. In this study, we investigated the response of the lysosome–autophagy system to three relevant types of ZnO particles, namely, a polydisperse mixture of bare, micron-sized particles (100–1000 nm) and monodisperse, bare, and coated (with triethoxycaprylylsilane) ZnO nanoparticles (85 nm). To investigate the molecular mechanisms mediating the response of the lysosome–autophagy system to these ZnO particles, we examined a complete set of markers of this pathway and characterized each step, from transcriptional activation to clearance of autophagic cargo. To evaluate the effect of the different types of ZnO particles on the lysosome–autophagy system, biological assays were conducted under conditions that do not cause considerable cytotoxicity. All three types of ZnO particles were found to result in activation of the transcription factor EB, a master regulator of autophagy and lysosomal biogenesis. Cellular exposure to bare and coated nano-sized ZnO enhanced the formation and turnover of autophagosomes and cellular clearance. Cellular exposure to the polydisperse mixture of ZnO particles, however, resulted in enhancement of autophagosome formation, but also in blockage of the autophagic flux. Results from this study underscore the importance of characterizing the autophagic response to ZnO-based materials and contribute significant engineering principles for the future design of nano- and micron-sized ZnO materials with the desired autophagy-modulating properties.

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Palladium nanoparticles induce autophagy and autophagic flux blockade in Hela cells

Abstract: Size-dependent autophagy and autophagic flux blockade in Hela cells by palladium nanoparticles.

Cited by 18 publications

References 50 publications

The palladacycle complex AJ-5 induces apoptotic cell death while reducing autophagic flux in rhabdomyosarcoma cells

The palladacycle complex AJ-5 induces apoptotic cell death while reducing autophagic flux in rhabdomyosarcoma cells

Nanoparticle Interactions with the Tumor Microenvironment

Zinc Oxide Particles Induce Activation of the Lysosome–Autophagy System

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