Mechanism of 5-Fluorouracil-Induced Apoptosis on Cultured Corneal Endothelial Cells

Hong, Show‐Jen; Wu, Wen-Chuan; Lai, Yu‐Hung; Wu, Kwou-Yeung

doi:10.4236/ojapo.2014.32002

Cited by 6 publications

(6 citation statements)

References 26 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In addition, the immunohistochemical results of the present work could reveal that capecitabine induced apoptosis in corneal epithelium, endothelium and keratocytes through up-regulation of p53 protein expression as indicated by the significant increase in the color intensity of p53 positive immunoreaction in capecitabine-treated group as compared to control group. This was in agreement with recent invitro studies that illustrated that 5-FU induced apoptosis in cultured corneal epithelial and endothelial cells through upregulation of apoptosis-related proteins mainly p53, p21 and Bax [59,60] . Other invitro study revealed that mitomycin C (an alkylating agent) induced apoptosis in cultured corneal keratocytes, and they attributed this to be due to the caspase cascade related to the mitochondrial pathway of apoptosis [61] .…”

Section: Discussionsupporting

confidence: 81%

The Potential Protective Role of Hesperidin Against Capecitabine-Induced Corneal Toxicity in Adult Male Albino Rat. Light and Electron Microscopic Study

Elwan

Kassab

2017

Egyptian Journal of Histology

View full text Add to dashboard Cite

Background: Capecitabine is a chemotherapeutic agent widely used for the treatment of malignancies. Ocular disorders have been reported with capecitabine therapy. Hesperidin is a naturally occurring compound derived mainly from citrus fruits and has a wide range of pharmacological activities and a proposed role in combating many ocular diseases. Aim: To evaluate the potential protective role of hesperidin against the corneal toxicity caused by capecitabine in adult male albino rats. Material and Methods: Thirty-six adult male albino rats were divided into four equal groups; control group, hesperidintreated group (50 mg/kg), capecitabine-treated group (40 mg/kg), and combination-treated "capecitabine and hesperidintreated" group. Animals were orally administered once daily for one month. Specimens from the cornea were processed for light and electron microscopy. Immunohistochemical study was performed using antibodies against p53. Results: Specimens from capecitabine-treated animals showed significant decrease of epithelial thickness. The corneal epithelial cells showed nuclear alteration and vacuolated cytoplasm. The stromal collagen fibers were irregularlyarranged and widely separated with neovascularization and mononuclear cellular infiltration. Ultrastructurally, focal widening of the intercellular spaces, partial loss of desmosomal junctions and swollen mitochondria were observed. The immunohistochemical study showed a significant increase in p53 immunoreaction. In contrast, minimal changes were observed in rats treated concomitantly with both capecitabine and hesperidin, with a non significant increase in the immunoreactions. Conclusion: Capecitabine induced structural changes in cornea of adult albino rat that could be ameliorated by concomitant treatment with hesperidin.

show abstract

Section: Discussionsupporting

confidence: 81%

The Potential Protective Role of Hesperidin Against Capecitabine-Induced Corneal Toxicity in Adult Male Albino Rat. Light and Electron Microscopic Study

Elwan

Kassab

2017

Egyptian Journal of Histology

View full text Add to dashboard Cite

show abstract

“…Both 5-FU and FO have been shown to enhance apoptosis by regulating the interplay between pro- and anti-apoptotic members of Bcl-2 family. 40,41 Therefore, we decided to investigate the effect of these treatments on the intrinsic and extrinsic apoptotic pathways. The extrinsic apoptotic pathway is stimulated by death receptors such as Fas and TNFR1, which constitutes a prominent mechanism in the defense against tumors.…”

Section: Discussionmentioning

confidence: 99%

“…An increase in Bcl-2 levels by 5-FU may be related to DNA damage, which induces the expression of a large number of pro-apoptotic genes, such as Bax, Noxa, and Puma, and represses Bcl-2 expression. 40,47,48 FO has been postulated to alter the structure of mitochondrial membrane by modifying its fatty acid composition and thereby the interaction between different Bcl-2 members. [49][50][51] Our results suggest Bcl-2 as a major player in regulation of apoptosis by both 5-FU and/or FO.…”

Section: Discussionmentioning

confidence: 99%

Apoptosis mediated chemosensitization of tumor cells to 5-fluorouracil on supplementation of fish oil in experimental colon carcinoma

et al. 2017

View full text Add to dashboard Cite

5-Fluorouracil has been considered as a cornerstone therapy for colorectal cancer; however, it suffers from low therapeutic response rate and severe side effects. Therefore, there is an urgent need to increase the clinical efficacy of 5-fluorouracil. Recently, fish oil rich in n-3 polyunsaturated fatty acids has been reported to chemosensitize tumor cells to anti-cancer drugs. This study is designed to understand the underlying mechanisms of synergistic effect of fish oil and 5-fluorouracil by evaluation of tumor cell-associated markers such as apoptosis and DNA damage. The colon cancer was developed by administration of N,N-dimethylhydrazine dihydrochloride and dextran sulfate sodium salt. Further these animals were treated with 5-fluorouracil, fish oil, or a combination of both. In carcinogen-treated animals, a decrease in DNA damage and apoptotic index was observed. There was also a decrease in the expression of Fas, FasL, caspase 8, and Bax, and an increase in Bcl-2. In contrast, administration of 5-fluorouracil and fish oil as an adjuvant increased both DNA damage and apoptotic index by activation of both extrinsic and intrinsic apoptotic pathways as compared to the other groups. The increased pro-apoptotic effect by synergism of 5-fluorouracil and fish oil may be attributed to the incorporation of n-3 polyunsaturated fatty acids in membrane, which alters membrane fluidity in cancer cells. In conclusion, this study highlights that the induction of apoptotic pathway by fish oil may increase the susceptibility of tumors to chemotherapeutic regimens.

show abstract

“…However, with the treatment of 5‐FU, the PRPS1 mutant cells proliferated more slowly than PRPS1 WT and control cells (Figure A, Figure E and F), suggesting the susceptibility of PRPS1 mutants to 5‐FU action. It has been shown that the cytotoxicity of 5‐FU is ascribed to the misincorporation of fluoronucleotides into RNA and DNA, leading to DNA damage response (DDR) and apoptosis . We therefore reasoned that PRPS1 mutant could allow enhanced apoptosis for Reh ALL cells with the treatment of 5‐FU.…”

Section: Resultsmentioning

confidence: 99%

“…It has been shown that the cytotoxicity of 5-FU is ascribed to the misincorporation of fluoronucleotides into RNA and DNA, leading to DNA damage response (DDR) and apoptosis. 15,16 We therefore reasoned that PRPS1 mutant could allow enhanced apoptosis for Reh ALL cells with the treatment of 5-FU. As shown in Figure 2B, 5-FU can readily induce apoptosis of Reh cells as speculated, and the cells harboring PRPS1 WT showed moderately increased apoptosis compared to the control cells.…”

Section: -Fu Promotes the Apoptosis Of Prps1 Mutant All Cellsmentioning

confidence: 99%

Increase of PRPP enhances chemosensitivity of PRPS1 mutant acute lymphoblastic leukemia cells to 5‐Fluorouracil

Wang

Yao

Fang

et al. 2018

J Cellular Molecular Medi

View full text Add to dashboard Cite

Relapse‐specific mutations in phosphoribosyl pyrophosphate synthetase 1 (PRPS1), a rate‐limiting purine biosynthesis enzyme, confer significant drug resistances to combination chemotherapy in acute lymphoblastic leukemia (ALL). It is of particular interest to identify drugs to overcome these resistances. In this study, we found that PRPS1 mutant ALL cells specifically showed more chemosensitivity to 5‐Fluorouracil (5‐FU) than control cells, attributed to increased apoptosis of PRPS1 mutant cells by 5‐FU. Mechanistically, PRPS1 mutants increase the level of intracellular phosphoribosyl pyrophosphate (PRPP), which causes the apt conversion of 5‐FU to FUMP and FUTP in Reh cells, to promote 5‐FU‐induced DNA damage and apoptosis. Our study not only provides mechanistic rationale for re‐targeting drug resistant cells in ALL, but also implicates that ALL patients who harbor relapse‐specific mutations of PRPS1 might benefit from 5‐FU‐based chemotherapy in clinical settings.

show abstract

Mechanism of 5-Fluorouracil-Induced Apoptosis on Cultured Corneal Endothelial Cells

Abstract: Abstract

Cited by 6 publications

References 26 publications

The Potential Protective Role of Hesperidin Against Capecitabine-Induced Corneal Toxicity in Adult Male Albino Rat. Light and Electron Microscopic Study

The Potential Protective Role of Hesperidin Against Capecitabine-Induced Corneal Toxicity in Adult Male Albino Rat. Light and Electron Microscopic Study

Apoptosis mediated chemosensitization of tumor cells to 5-fluorouracil on supplementation of fish oil in experimental colon carcinoma

Increase of PRPP enhances chemosensitivity of PRPS1 mutant acute lymphoblastic leukemia cells to 5‐Fluorouracil

Contact Info

Product

Resources

About