Targeting of epidermal growth factor receptor by cyclopentenone prostaglandin 15-Deoxy-Δ12,14-prostaglandin J2 in human oral squamous carcinoma cells

Siavash, Hessam; Nikitakis, Nikolaos G.; Sauk, John J.

doi:10.1016/j.canlet.2004.02.003

Cited by 7 publications

(12 citation statements)

References 28 publications

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“…The intracellular uptake of Pc 4 was monitored for incubation times of 2, 4, 6 and 24 hours. The SCC-15 cell line is well-known for its high EGFR expression, particularly among H&N SCC lines 36 . As evident from the results shown in Figure 2, the EGFR-targeted nanoformulation is much faster rate compared to the nontargeted formulation within the first 8 hrs.…”

Section: Resultsmentioning

confidence: 99%

“…Furthermore, future studies will be focused on orthotopic models of H&N SCCs where targeted nanomedicine strategies for photosensitizer delivery can be integrated with specialized fiber-optic technologies for light delivery, to evaluate the translational capabilities. In addition, our EGFR-targeted photodynamic nanomedicine formulation can become potentially applicable toward developing PDT strategies for several other EGFR-overexpressing tumors 36 .…”

Section: Discussionmentioning

confidence: 99%

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A Cell-Targeted Photodynamic Nanomedicine Strategy for Head and Neck Cancers

et al. 2013

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Photodynamic Therapy (PDT) holds great promise for the treatment of head and neck (H&N) carcinomas where repeated loco-regional therapy often becomes necessary due to the highly aggressive and recurrent nature of the cancers. While interstitial light delivery technologies are being refined for PDT of H&N and other cancers, a parallel clinically relevant research area is the formulation of photosensitizers in nanovehicles that allow systemic administration yet preferential enhanced uptake in the tumor. This approach can render dual-selectivity of PDT, by harnessing both the drug and the light delivery within the tumor. To this end, we report on a cell-targeted nanomedicine approach for the photosensitizer silicon phthalocyanine-4 (Pc 4), by packaging it within polymeric micelles that are surface-decorated with GE11-peptides to promote enhanced cell-selective binding and receptor-mediated internalization in EGFR-overexpressing H&N cancer cells. Using fluorescence spectroscopy and confocal microscopy, we demonstrate in vitro that the EGFR-targeted Pc 4-nanoformulation undergoes faster and higher uptake in EGFR-overexpressing H&N SCC-15 cells. We further demonstrate that this enhanced Pc 4 uptake results in significant cell-killing and drastically reduced post-PDT clonogenicity. Building on this in vitro data, we demonstrate that the EGFR-targeted Pc 4-nanoformulation results in significant intra-tumoral drug uptake and subsequent enhanced PDT response, in vivo, in SCC-15 xenografts in mice. Altogether our results show significant promise towards a cell-targeted photodynamic nanomedicine for effective treatment of H&N carcinomas.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

A Cell-Targeted Photodynamic Nanomedicine Strategy for Head and Neck Cancers

et al. 2013

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“…Straus et al (46) also showed that up to 50-fold more cyclopentenone was needed to achieve the same extent of inhibition of NFB DNA binding ability by 15d-PGJ 2 . Interestingly, on the contrary, 9,10-dihydro-15d-PGJ 2 was unable to repress EGFR expression as did 15d-PGJ 2 in human oral squamous carcinoma cells (5). Collectively, these results suggest that alkylation by these two reactive centers might lead to differential outcomes downstream.…”

Section: Discussionmentioning

confidence: 64%

“…It was also found that, independent of PPAR␥, 15d-PGJ 2 could block the NFB-mediated pathway and activate phosphatidylinositol 3 kinase and, in turn, the MAPK (mitogen-activated protein kinase) kinase cascade (3)(4)(5)40). Interestingly, it was also found that ⌬ 12 -PGJ 2 , an analog of 15d-PGJ 2 , inhibits isopeptidase activity in ubiquitin-mediated proteasomal degradation, crippling proteasomal function (41).…”

Section: Discussionmentioning

confidence: 93%

“…PGD 2 can undergo dehydration reactions to yield the J 2 series of prostaglandins, including PGJ 2 , ⌬ 12,14 -PGJ 2 , and 15d-PGJ 2 (1). The J 2 series of prostaglandins influences multiple signaling pathways by covalently binding with key signaling molecules (2)(3)(4)(5)(6). Among them, 15d-PGJ 2 has displayed highest potency as an inducer of gene expression.…”

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confidence: 99%

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Nrf2-mediated Induction of Cytoprotective Enzymes by 15-Deoxy-Δ12,14-Prostaglandin J2 Is Attenuated by Alkenal/one Oxidoreductase

Xiang

Egner

Wakabayashi

et al. 2006

Journal of Biological Chemistry

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NADPH-dependent alkenal/one oxidoreductase (Aor) was discovered to be highly inducible in rat liver following treatment with the cancer chemopreventive agent 3H-1, 2-dithiole-3-thione. Aor was further characterized as an Nrf2-regulated antioxidative enzyme that reduces carbon-carbon double bonds in a variety of ␣, ␤-unsaturated aldehydes and ketones. 15-Deoxy-⌬ 12,14 -prostaglandin J 2 (15d-PGJ 2 ) is a reactive membrane lipid metabolite that activates multiple pathways, including Nrf2-mediated induction of cytoprotective enzymes. Physiologically, it is postulated that 15d-PGJ 2 alkylates key regulatory proteins via the electrophilic carbon centers found in two ␣, ␤-unsaturated ketone moieties. This current study addresses the metabolism of 15d-PGJ 2 by rat Aor (rAor) and subsequent deactivation of the Nrf2 signaling pathway by both rat and human AOR. We demonstrate that induction of NADPHdependent quinone oxidoreductase activity by 15d-PGJ 2 is markedly attenuated in mouse embryonic fibroblasts that overexpress rAor. Luciferase reporter assay and quantitative real-time PCR confirmed these findings. Concentrations required for doubling the NADPH-dependent quinone oxidoreductase response are increased from 1.8 M in wild-type to >10 M in rat Aor transgenic fibroblasts. 15d-PGJ 2 is metabolized by recombinant rAor with a K m of 9.6 M and k cat of 18.5 min ؊1. The major product is 12,13-dihydro-15-deoxy-⌬ 12,14 -prostaglandin J 2 (dihydro-15d-PGJ 2 ). The reduction of C‫؍‬C by Aor yielding dihydro-15d-PGJ 2 abolishes the inducibility in an antioxidant response element-driven luciferase assay. Collectively, these results demonstrate that 15d-PGJ 2 can be catabolized by Aor, thereby attenuating subsequent Nrf2 signaling and possibly inflammatory and apoptotic processes also influenced by 15d-PGJ 2 . Prostaglandins (PG)2 are a subfamily of eicosanoids shown to regulate a variety of physiological processes, including growth, differentiation, vascular constriction, inflammation, and homeostasis. Prostaglandins are primarily derived from arachidonic acid following phospholipase-catalyzed release from membrane lipids. Arachidonic acid is converted by cyclooxygenases into PGH 2 , which is further metabolized into PGD 2 , PGE 2 , prostacyclin, or thromboxane via various prostaglandin synthases. PGD 2 can undergo dehydration reactions to yield the J 2 series of prostaglandins, including PGJ 2 , ⌬ 12,14 -PGJ 2 , and 15d-PGJ 2 (1). The J 2 series of prostaglandins influences multiple signaling pathways by covalently binding with key signaling molecules (2-6). Among them, 15d-PGJ 2 has displayed highest potency as an inducer of gene expression. Discovered as an agonist for peroxisome-proliferator-activated receptor ␥ (PPAR␥), 15d-PGJ 2 was shown to modulate the expression of genes containing a peroxisome-proliferator response element in the promoter region, resulting in adipocyte differentiation (7). In addition, 15d-PGJ 2 contains two ␣,␤-unsaturated ketone moieties in tandem within its structure. These moieties covalently modi...

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