Indomethacin increases the cytotoxicity of cis-platinum and 5-fluorouracil in the human uterine cervical cancer cell lines SKG-2 and HKUS by increasing the intracellular uptake of the agents

Ogino, Mitsuharu; Minoura, Shigeki

doi:10.1007/pl00012088

Cited by 20 publications

(10 citation statements)

References 18 publications

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“…Applying low dose indomethacin (2.8 μM) after 72 h a significant (∼60%) IC 50 reduction was reported after 5-FU treatment on murine Colon 26 cells [28], which constitutively express COX-2 protein [32]. Similar results were found on SKG-2 and HKUS human cervical cancer cells after treatment with indomethacin (0.3 μM), which significantly increased the cytotoxicity of [29]. However, the COX-2 expression level of these cells are unknown.…”

Section: Cox-2 Protein Expression Determined By Western Blotting and supporting

confidence: 83%

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Enhancement of 5-Fluorouracil Efficacy on High COX-2 Expressing HCA-7 Cells by Low Dose Indomethacin and NS-398 but not on Low COX-2 Expressing HT-29 Cells

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Pap

et al. 2008

Pathol. Oncol. Res.

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The antiproliferative effect of 5-fluorouracil (5-FU) in the presence of low dose non-steroidal anti-inflammatory drugs (NSAIDs) on high cyclooxygenase-2 (COX-2)-expressing HCA-7 and low COX-2-expressing HT-29 colon carcinoma cell lines was investigated. Pharmacogenetic parameters were studied to characterize the 5-FU sensitivity of the two cell lines. Thymidylate synthase (TS) and methylenetetrahydrofolate reductase (MTHFR) polymorphisms were determined by PCR analysis. Cell proliferation was measured by SRB assay, cell cycle distribution and apoptosis by FACS analysis. Cyclooxygenase expression was detected by Western blot and also by fluorescence microscopy. Prostaglandin E(2) (PGE(2)) levels were investigated with ELISA kit. The HT-29 cell line was found to be homozygous for TS 2R and 1494ins6 and T homozygous for MTHFR 677 polymorphisms predicting high 5-FU sensitivity (IC(50): 10 microM). TS 3R homozygosity, TS 1496del6 and MTHFR 677CT heterozygosity may explain the modest 5-FU sensitivity (IC(50): 1.1 mM) of the HCA-7 cell line. Indomethacin and NS-398 (10 microM and 1.77 microM, respectively) reduced the PGE(2) level in HCA-7 cells (>90%). Low concentrations of NSAIDs without antiproliferative potency increased the S-phase arrest and enhanced the cytotoxic action of 5-FU only in HCA-7 cells after 48-hours treatment. The presented data suggested that the enhancement of 5-FU cytotoxicity by indomethacin or NS-398 applied in low dose is related to the potency of NSAIDs to modulate the cell-cycle distribution and the apoptosis; however, it seems that this effect might be dependent on cell phenotype, namely on the COX-2 expression.

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Section: Cox-2 Protein Expression Determined By Western Blotting and supporting

confidence: 83%

“…Specifically, combining flurbiprofen, sulindac or indomethacin with methotrexate, cyclophosphamide, melphalan, vincristine, doxorubicin and 5-FU resulted in an enhancement of cytotoxicity [26][27][28][29].…”

Section: Cox-2 Protein Expression Determined By Western Blotting and mentioning

confidence: 98%

Enhancement of 5-Fluorouracil Efficacy on High COX-2 Expressing HCA-7 Cells by Low Dose Indomethacin and NS-398 but not on Low COX-2 Expressing HT-29 Cells

Réti

Barna

Pap

et al. 2008

Pathol. Oncol. Res.

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“…using other non-steroidal anti-inflammatory drugs (Ogino and Hanazono, 1999;Ogino and Minoura, 2001;Mizutani et al, 2002). This may account for some of the increased tumor regression seen with the combination treatments, since the direct addition of celecoxib to 5-FU (5-FU/ celecoxib) was more effective in destroying tumors than when the treatments were given separately (5-FU þ celecoxib).…”

Section: Figurementioning

confidence: 94%

Treatment with 5-Fluorouracil and Celecoxib Displays Synergistic Regression of Ultraviolet Light B-Induced Skin Tumors

Wilgus

Breza

Tober

et al. 2004

Journal of Investigative Dermatology

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Standard chemotherapeutic agents used for the treatment of pre-cancerous skin lesions and non-melanoma skin cancers are not completely effective. Several studies have suggested that repeated inflammatory sunburn reactions, which include the induction of cyclooxygenase-2 (COX-2) and the subsequent production of prostaglandins, play a role in skin cancer development. COX-2 inhibition has been demonstrated to be a potent means of preventing skin cancer development in mice; however, COX-2 inhibitors alone are not effective as chemotherapeutic agents. Data in a variety of cancer types suggest greater efficacy in treating tumors with combination chemotherapies. Therefore, we hypothesized that a combination of the chemotherapeutic agent 5-fluorouracil (5-FU) and the COX-2 inhibitor and anti-inflammatory drug celecoxib would act synergistically to regress tumors in a murine model of ultraviolet light B- (UVB-) induced carcinogenesis. We found that topical treatment with 5-FU and celecoxib together was up to 70% more effective in reducing the number of UVB-induced skin tumors than 5-FU treatment alone. Our data suggest that more effective chemotherapy regimens can be developed to treat the millions of pre-cancerous and cancerous skin lesions that arise every year, which could ultimately lead to a significant reduction in costs and cosmetic defects (scarring) associated with surgical interventions.

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“…cytotoxicity [24]. An impressive but interestingly non-significant tumor volume decrease (40%) after 28-day low dose ibuprofen+5-FU treatment in a COX-2-expressing mouse colorectal tumor modell was described [25].…”

Section: Discussionmentioning

confidence: 98%

Enhanced 5-fluorouracil cytotoxicity in high cyclooxygenase-2 expressing colorectal cancer cells and xenografts induced by non-steroidal anti-inflammatory drugs via downregulation of dihydropyrimidine dehydrogenase

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Pap

Adleff

et al. 2009

Cancer Chemother Pharmacol

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Indomethacin increases the cytotoxicity of cis-platinum and 5-fluorouracil in the human uterine cervical cancer cell lines SKG-2 and HKUS by increasing the intracellular uptake of the agents

Cited by 20 publications

References 18 publications

Enhancement of 5-Fluorouracil Efficacy on High COX-2 Expressing HCA-7 Cells by Low Dose Indomethacin and NS-398 but not on Low COX-2 Expressing HT-29 Cells

Enhancement of 5-Fluorouracil Efficacy on High COX-2 Expressing HCA-7 Cells by Low Dose Indomethacin and NS-398 but not on Low COX-2 Expressing HT-29 Cells

Treatment with 5-Fluorouracil and Celecoxib Displays Synergistic Regression of Ultraviolet Light B-Induced Skin Tumors

Enhanced 5-fluorouracil cytotoxicity in high cyclooxygenase-2 expressing colorectal cancer cells and xenografts induced by non-steroidal anti-inflammatory drugs via downregulation of dihydropyrimidine dehydrogenase

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