Effects of Capecitabine and Celecoxib in Experimental Pancreatic Cancer

Arjona‐Sánchez, Álvaro; Ruiz-Rabelo, Juan; Perea, Milagrosa; Vázquez, Rafael; Cruz, Antonio Míguez Santa; Muñoz, María del Carmen; Túnez, Isaac; Muntané, Jordi; Padillo, Francisco J.

doi:10.1159/000288708

Cited by 20 publications

(16 citation statements)

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“…In an experimental pancreatic cancer model, N-nitrosobis(2-oxopropyl)amine has been shown to induce an increase in lipoperoxides and a reduction in antioxidants in the pancreas. This indicates that there is a close association between oxidative stress and pancreatic cancer ( 18 ). The present study suggests that reactive oxygen species may induce the destruction of the cytoskeleton in epithelial cells, followed by the activation of NF-κB, which is important for the progression of pancreatic cancer.…”

Section: Discussionmentioning

confidence: 93%

Impact of oxidative stress on the cytoskeleton of pancreatic epithelial cells

2014

Experimental and Therapeutic Medicine

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In the present study the effect of reactive oxygen species on the morphological changes of pancreatic epithelial cells in a three-dimensional culture system was investigated. In addition, the expression of signaling molecules during this process was determined. Matrigel™ was used to construct a three-dimensional culture model of pancreatic epithelial and cancer cells. The cultured cells were stimulated with 1 or 200 μmol/l H2O2 (a typical reactive oxygen species), and the morphological changes were then evaluated after 15 min, 1 h and 4 h. The cytoskeleton of the cells was observed using laser scanning confocal microscopy with immunofluorescence staining. In addition, the nuclear content of nuclear factor κ-light-chain-enhancer of activated B cells (NF-κB) was detected using ELISA. The results demonstrated that treatment with 200 μmol/l H2O2 induced cell contraction after 15 min, and cell morphology recovered after 1 h; however, cell size was reduced after 4 h. Consequently, intracellular actin and microtubules were rapidly lost following H2O2 treatment, and the cytoskeleton became indistinct and eventually disintegrated after 4 h. Similar observations were noted for the normal pancreatic epithelial and cancer cells. By contrast, treatment with 1 μmol/l H2O2 did not affect the morphology and cytoskeleton of pancreatic epithelial cells. In addition, 200 μmol/l H2O2 treatment increased the activity of NF-κB gradually, while 1 μmol/l H2O2 treatment was found to have little impact on the activity of NF-κB. Therefore, it was demonstrated that oxidative stress can induce the early onset of reversible cell contraction and cytoskeleton depolarization in pancreatic epithelial cells, and can increase NF-κB expression.

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Section: Discussionmentioning

confidence: 93%

Impact of oxidative stress on the cytoskeleton of pancreatic epithelial cells

2014

Experimental and Therapeutic Medicine

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“…Several studies have indicated that COX-2 expression is high in both chronic pancreatitis and PDAC therefore suggesting a potential role in fibrosis (6,29). COX-2 levels are also known to positively correlate with the aggressiveness of PDAC (30) and that blocking COX-2 significantly reduces pancreatic tumor size and metastatic potential (31) in animal models. No studies to date, however, have examined the downstream role of PGE 2 or the EP receptors in HPSCs.…”

Section: Discussionmentioning

confidence: 99%

Prostaglandin E2 Regulates Pancreatic Stellate Cell Activity Via the EP4 Receptor

et al. 2013

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Objectives Pancreatic stellate cells are source of dense fibrotic stroma, a constant pathological feature of chronic pancreatitis (CP) and pancreatic adenocarcinoma (PDAC). We observed correlation between levels of cyclooxygenase-2 (COX-2) and its product prostaglandin E2 (PGE2) and the extent of pancreatic fibrosis. Aim of this study was to delineate the effects of PGE2 on immortalized human pancreatic stellate cells (HPSC) and to identify the receptor involved. Methods IHC, RT-PCR and Q-RT-PCR were used to assess COX-2, extracellular matrix (ECM) and matrix metalloproteinases (MMP) gene expression. Eicosanoid profile was determined by LC/MS/MS. HPSC proliferation was assessed by MTS assay; migration by Boyden chamber assay and invasion using an invasion chamber. Transient silencing was obtained by siRNA. Results HPSC express COX-2 and synthesize PGE2. PGE2 stimulated HPSC proliferation, migration and invasion; stimulated expression of both ECM and MMP genes. HPSC expressed all four EP receptors. Only blocking the EP4 receptor resulted in abrogation of PGE2 mediated HPSC activation. Specificity of EP4 for the effects of PGE2 on stellate cells was confirmed using specific antagonists. Conclusion Our data indicate that PGE2 regulates PSC profibrotic activities via EP4 receptor thus suggesting EP4 receptor as useful therapeutic target for pancreatic cancer to reduce desmoplasia.

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“…Some of them are new molecules as Meroxest, a synthetic merosesquiterpene derivative of the trans -communic acid, plentiful in Cupressus sempervirens [ 176 ], or Jadomycin, which is synthesized by the bacteria Streptomyces venezuelae [ 177 ]. Other compounds are part of the current therapeutic repertoire, like oxaliplatin [ 178 ], bleomycin [ 179 ], gemcitabine [ 180 , 181 ], cyclophosphamide [ 182 ], celecoxib [ 183 ], capecitabine [ 184 , 185 ], bortezomib (a proteasome inhibitor, approved for the treatment of multiple myeloma) [ 186 , 187 ], and arsenic trioxide (ATO). ATO, which is used in the treatment of acute promyelocytic leukemia (APL), can produce a loss of permeability of the outer mitochondrial membrane and impair the function of the respiratory chain, leading to an increase in superoxide anion [ 188 – 191 ].…”

Section: Antitumor Therapy Oxidative Stress and Interactions Witmentioning

confidence: 99%

Antioxidant Intake and Antitumor Therapy: Toward Nutritional Recommendations for Optimal Results

Mut-Salud

Álvarez

Garrido

et al. 2015

Oxidative Medicine and Cellular Longevity

141

104

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The role of the induction of oxidative stress as the mechanism of action of many antitumor drugs is acquiring an increasing interest. In such cases, the antitumor therapy success may be conditioned by the antioxidants present in our own body, which can be synthesized de novo (endogenous) or incorporated through the diet and nutritional supplements (exogenous). In this paper, we have reviewed different aspects of antioxidants, including their classification, natural sources, importance in diet, consumption of nutritional supplements, and the impact of antioxidants on health. Moreover, we have focused especially on the study of the interaction between antioxidants and antitumor therapy, considering both radiotherapy and chemotherapy. In this regard, we found that the convenience of administration of antioxidants during cancer treatment still remains a very controversial issue. In general terms, antioxidants could promote or suppress the effectiveness of antitumor treatment and even protect healthy tissues against damage induced by oxidative stress. The effects may depend on many factors discussed in the paper. These factors should be taken into consideration in order to achieve precise nutritional recommendations for patients. The evidence at the moment suggests that the supplementation or restriction of exogenous antioxidants during cancer treatment, as appropriate, could contribute to improving its efficiency.

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Effects of Capecitabine and Celecoxib in Experimental Pancreatic Cancer

Cited by 20 publications

References 50 publications

Impact of oxidative stress on the cytoskeleton of pancreatic epithelial cells

Impact of oxidative stress on the cytoskeleton of pancreatic epithelial cells

Prostaglandin E2 Regulates Pancreatic Stellate Cell Activity Via the EP4 Receptor

Antioxidant Intake and Antitumor Therapy: Toward Nutritional Recommendations for Optimal Results

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