Nitric Oxide-Releasing Silica Nanoparticle Inhibition of Ovarian Cancer Cell Growth

Stevens, Ellen V.; Carpenter, Alexis W.; Shin, Jae Ho; Liu, Jinsong; Der, Channing J.; Schoenfisch, Mark H.

doi:10.1021/mp9002865

Cited by 99 publications

(72 citation statements)

References 52 publications

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“…Macromolecular scaffolds capable of effectively storing and releasing NO have been developed to enable local delivery (27,28). The most promising NO release vehicles to date include NO donor-modified N-diazeniumdiolate silica nanoparticles (29)(30)(31), dendrimers (32)(33)(34)(35)(36), and chitosan (15). While silica nanoparticles (14,(37)(38)(39) and dendrimers (32)(33)(34) are effective as antimicrobials, they do not easily break down and thus have limited potential as inhaled therapeutics.…”

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confidence: 99%

Antibacterial Action of Nitric Oxide-Releasing Chitosan Oligosaccharides against Pseudomonas aeruginosa under Aerobic and Anaerobic Conditions

Reighard

2015

Antimicrob Agents Chemother

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Chitosan oligosaccharides were modified with N-diazeniumdiolates to yield biocompatible nitric oxide (NO) donor scaffolds. The minimum bactericidal concentrations and MICs of the NO donors against Pseudomonas aeruginosa were compared under aerobic and anaerobic conditions. Differential antibacterial activities were primarily the result of NO scavenging by oxygen under aerobic environments and not changes in bacterial physiology. Bacterial killing was also tested against nonmucoid and mucoid biofilms and compared to that of tobramycin. Smaller NO payloads were required to eradicate P. aeruginosa biofilms under anaerobic versus aerobic conditions. Under oxygen-free environments, the NO treatment was 10-fold more effective at killing biofilms than tobramycin. These results demonstrate the potential utility of NO-releasing chitosan oligosaccharides under both aerobic and anaerobic environments. Pseudomonas aeruginosa is an opportunistic human pathogen that frequently colonizes people with compromised immune systems, such as those with cystic fibrosis (CF) or severe burn wounds (1). The success of P. aeruginosa as a pathogen is related to its multitude of virulence factors, which increase adherence to the host cells, induce inflammation, and disrupt the host immune response (1). Furthermore, P. aeruginosa is intrinsically resistant to many antibiotics due to low membrane permeability and increased expression of ␤-lactamases and efflux pumps (2-4). In addition to this native resistance, P. aeruginosa readily adapts to antibiotic challenge by acquiring resistance genes (3, 5) and forming protective, cooperative communities known as biofilms (6, 7).While all antibiotic resistance mechanisms are not fully understood, at least three main factors reduce antibiotic efficacy against bacterial biofilms compared to planktonic cells. First, P. aeruginosa in biofilms secretes a protective layer of exopolysaccharides that prevent the diffusion of antibiotics (7). In the context of cystic fibrosis, biofilm-bound P. aeruginosa exists predominantly as the mucoid phenotype, characterized by a secreted alginate matrix that provides a physical barrier against the host immune response and antibiotics (8). This exopolysaccharide matrix also prevents the diffusion of oxygen into biofilms, causing P. aeruginosa to switch from aerobic to anaerobic respiration (9). The reduced metabolic activity of P. aeruginosa undergoing anaerobic respiration protects the bacterium against traditional antibiotics that are most effective against rapidly dividing cells, including aminoglycosides and ␤-lactams (10, 11). Finally, biofilms produce persister cells (i.e., dormant bacteria that are highly resistant to chemical disinfectants and exhibit multidrug tolerance) much more frequently than planktonic bacterial cultures (3, 7).The failure of conventional antibiotics to treat P. aeruginosa biofilms and infections necessitates the development of new antibacterial agents. Nitric oxide (NO), an endogenously produced free radical that can disperse (12, 13) and ...

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confidence: 99%

Antibacterial Action of Nitric Oxide-Releasing Chitosan Oligosaccharides against Pseudomonas aeruginosa under Aerobic and Anaerobic Conditions

Reighard

2015

Antimicrob Agents Chemother

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“…NO, a gaseous free radical, positively or negatively modulates cancer progression and metastasis (18). Several studies demonstrate that NO plays an important role in ovarian cancer progression (27)(28)(29). Furthermore, the intron 4 polymorphism of NO synthase in ovarian cancer patients is associated with advanced tumor stage and a high rate of pelvic lymph node metastasis (30).…”

Section: Discussionmentioning

confidence: 99%

Sepiapterin inhibits cell proliferation and migration of ovarian cancer cells via down-regulation of p70S6K-dependent VEGFR-2 expression

Cho

Kim²,

Ko³

et al. 2011

Oncol Rep

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Abstract. Tetrahydrobiopterin (BH 4 ) is known to be an essential cofactor for the aromatic amino acid hydroxylases, which are involved in the production of neurotransmitters, and for nitric oxide (NO) synthase. In the present study, we report that sepiapterin, the more stable form of the BH 4 precursor, modulates ovarian cancer cell proliferation and migration by NO-dependent and -independent mechanisms. Sepiapterin induction of cell proliferation and migration in SKOV-3 cells is accompanied by ERK, Akt and p70 S6K activation. These stimulatory effects of sepiapterin are reversed by pretreatment with NO synthase inhibitor. We also show that sepiapterin significantly inhibits vascular endothelial growth factor-A (VEGF-A)-stimulated cell proliferation and migration. Pretreatment with NO synthase inhibitor does not alter the ability of sepiapterin to inhibit VEGF-A-induced cell proliferation and migration, indicating that the suppressive effects of sepiapterin on VEGF-A-induced responses are mediated by a NO-independent mechanism. Finally, we demonstrate that sepiapterin markedly suppresses VEGF-A-induced p70 S6K phosphorylation and VEGFR-2 expression, resulting in inhibition of VEGF-A-induced cell proliferation and migration. Collectively, these findings represent a biphasic effect of sepiapterin on cellular fates, depending on the presence of growth factors, and support further development and evaluation of sepiapterin for the treatment of cancers overexpressing VEGFR-2.

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“…Drug delivery carriers may help overcome these limitations and salvage NO-based therapies to control MDSCs in TME. Ellen V. S. et al reported that silica nanoparticles encapsulated with NO-releasing derivative of pyrollidone could inhibit the growth of ovarian cancer cells in vitro [171]. Elevated expression of COX-2 receptor on MDSCs is associated with their immunosuppressive functions.…”

Section: Soluble Mediatorsmentioning

confidence: 99%

Nanoparticulate immunotherapy for cancer

Kapadia

Perry

Tian

et al. 2015

Journal of Controlled Release

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Nitric Oxide-Releasing Silica Nanoparticle Inhibition of Ovarian Cancer Cell Growth

Cited by 99 publications

References 52 publications

Antibacterial Action of Nitric Oxide-Releasing Chitosan Oligosaccharides against Pseudomonas aeruginosa under Aerobic and Anaerobic Conditions

Antibacterial Action of Nitric Oxide-Releasing Chitosan Oligosaccharides against Pseudomonas aeruginosa under Aerobic and Anaerobic Conditions

Sepiapterin inhibits cell proliferation and migration of ovarian cancer cells via down-regulation of p70S6K-dependent VEGFR-2 expression

Nanoparticulate immunotherapy for cancer

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