Enhancement of 5-fluorouracil-induced cytotoxicity by leucovorin in 5-fluorouracil-resistant gastric cancer cells with upregulated expression of thymidylate synthase

Nakamura, Ayako; Nakajima, Go; Okuyama, Ryuji; Kuramochi, Hidekazu; Kondoh, Yurin; Kanemura, Toshinori; Takechi, Teiji; Yamamoto, Masakazu; Hayashi, Kazuhiko

doi:10.1007/s10120-013-0249-7

Cited by 31 publications

(38 citation statements)

References 34 publications

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“…High expression levels of survivin and TS are associated with chemoresistance (24,28). In the present study, it was found that combined 5-FU and GA treatment further decreased the RNA and protein levels of survivin and TS compared with either monotherapy, consistent with improved chemoresistance and enhanced anticancer effects.…”

Section: Discussionsupporting

confidence: 68%

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Gambogic acid potentiates the chemosensitivity of colorectal cancer cells to 5-fluorouracil by inhibiting proliferation and inducing apoptosis

Wei

Yang

et al. 2017

Experimental and Therapeutic Medicine

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Abstract. Chemotherapy using 5-fluorouracil (5-FU) for colorectal cancer (CRC) has low specificity and response rates, leading to severe side effects. Gambogic acid (GA), a traditional Chinese medicine, has multi-targeted anticancer effects, including growth inhibition and apoptosis induction. However, it is unclear whether a combination of 5-FU and GA has synergistic anticancer effects in CRC cells. In this study, SW480 and HCT116 human CRC cells and human intestinal epithelial cells (IECs) were treated with different concentrations of 5-FU, GA or 5-FU+GA. A Cell Counting kit-8 assay was conducted to quantify cell proliferation. The combination index (CI) was calculated and the median-effect principle was applied to analyze the interaction between 5-FU and GA. Flow cytometry was used to determine the percentage of cells undergoing apoptosis. Reverse transcription-quantitative polymerase chain reaction and western blotting were applied to measure P53, survivin and thymidylate synthase (TS) mRNA and protein levels. It was found that 5-FU+GA more pronouncedly inhibited cell growth and induced apoptosis, compared with either monotherapy. CI values <1 indicated the synergistic effects of the drugs. 5-FU+GA further decreased P53, survivin and TS mRNA and protein levels in the two CRC cell lines compared with single drugs, whereas increased P53 protein levels were observed in HCT116 cells. Moreover, 5-FU+GA did not increase cytotoxicity to IECs. These results demonstrate that GA enhances the anticancer effects of 5-FU on CRC cells. Combined treatment with 5-FU and GA is effective and safe for CRC cells, and may become a promising chemotherapy treatment. IntroductionColorectal cancer (CRC) is one of the most commonly diagnosed malignancies and a leading cause of cancer-related mortality worldwide (1). China has a high incidence of CRC; with 149,722 estimated mortalities in 2011, it represents one-fifth of all cancers in terms of both morbidity and mortality (2).Treatment options for CRC include surgery, chemotherapy and radiotherapy. Surgical resection is the main and most effective option (3). However, surgery alone is insufficient to treat CRC, and certain patients do not have the opportunity to undergo surgical treatment (4). Systemic chemotherapy is an important tool, particularly for patients with advanced CRC: it can decrease clinical symptoms, improve the quality of life, and prolong survival (5).5-Fluorouracil (5-FU)-based chemotherapeutics are commonly used in CRC (6), with a single drug response rate of ~21% (7). Clinicians have used oxaliplatin (4) or irinotecan (8) in combination with 5-FU to enhance chemotherapeutic effects, but have only obtained response rates of 30-50% (4). In addition, these drugs have low specificity; although they increase 5-FU activity, they also promote damage to normal cells, and side effects are prominent (9).Therefore, the development of novel chemotherapy strategies is essential. Several studies (10)(11)(12)

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Section: Discussionsupporting

confidence: 68%

“…5-FU exerts cytotoxicity by inhibiting TS activity and interrupting DNA and RNA syntheses (27). High TS expression is also associated with 5-FU resistance (28) and poor prognosis (29).…”

Section: Introductionmentioning

confidence: 99%

Gambogic acid potentiates the chemosensitivity of colorectal cancer cells to 5-fluorouracil by inhibiting proliferation and inducing apoptosis

Wei

Yang

et al. 2017

Experimental and Therapeutic Medicine

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“…The mechanisms of resistance to 5-FU, namely, enhanced activities of thymidylate synthase (TS) and dihydropyrimidine dehydrogenase (DPYD), are well known to endow cancer cells with resistance to 5-FU in vitro and in clinical studies (12)(13)(14)(15). Actually, 5-FU is used in combination with 5-chloro-2,4-dihydroxypyridine, which is a DPYD inhibitor.…”

Section: Introductionmentioning

confidence: 99%

Establishment of a 5-fluorouracil-resistant triple-negative breast cancer cell line

Takahashi

Tanaka

Inagaki

et al. 2013

International Journal of Oncology

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Triple-negative breast cancers (TNBCs) are defined as tumors that lack expression of estrogen receptor, progesterone receptor and human epidermal growth factor receptor 2. Clinically, TNBC patients are treated with cytotoxic drugs including 5-fluorouracil (5-FU). However, TNBCs develop resistance to such drugs after a series of treatments. To elucidate the mechanisms of drug resistance, establishment of drug-resistant cancer cell lines should be one of the most useful model systems. However, 5-FU-resistant TNBC cell lines have not been previously reported. In this study, we established a 5-FU-resistant cell line, MDA-MB-231/5-FU, from the human TNBC cell line MDA-MB-231, by repeated exposure to stepwise increases in the concentration of 5-FU. The IC₅₀ value of 5-FU for MDA-MB-231/5-FU was 5.5-fold that for the parental cells. The MDA-MB-231/5-FU cell line acquired resistance to not only 5-FU, but also vinorelbine, paclitaxel and gemcitabine. Additionally, we performed iTRAQ-based quantitative proteomics in MDA-MB-231/5-FU cells and the parental cells in order to characterize MDA-MB-231/5-FU. The proteins upregulated in the newly established cells were mainly classified into the categories of 'DNA recombination', 'cell cycle', 'complex assembly', 'cytoskeleton organization', 'transport' and 'negative regulation of cell death'. These proteins may be related to mechanisms of drug resistance in TNBCs. Our established MDA-MB-231/5-FU cell line should be a useful tool for identifying new mechanisms of drug resistance and new drug targets in TNBCs.

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“…Different drugs may finally induce the MDR phenotype but through various signaling pathways, consequently leading to apparently different expression or functional changes of involved molecules. Previous studies have shown that several known proteins (such as P-glycoprotein, RhoE, GAS1, thymidylate synthase Bax and Bcl-2) play an important role in development of VCR-, 5-fluorouracil-or doxorubicin-based MDR phenotype gastric cancer cells (6,(28)(29)(30)(31), therefore, we speculate that different chemosensitizers may work through these known or some unknown ways to restore chemosensitivity of tumor MDR cells. Cisplatin, cis-diamminedichloroplatinum (CDDP), is deemed to be the 'penicillin of cancer drugs' due to its universal, early, and effective treatment for many cancers, including gastric cancer (32).…”

Section: Discussionmentioning

confidence: 82%

Adenovirus-mediated IL-24 expression enhances the chemosensitivity of multidrug-resistant gastric cancer cells to cisplatin

et al. 2013

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Abstract. Chemotherapy is one of the commonly used strategies in gastric cancer, especially for unresectable patients, but it becomes insensitive to repeated administration of even the most effective chemotherapeutic agents, such as cisplatin. Given this, there is an urgent need for developing chemosensitizers to overcome acquired resistance to chemotherapeutic agents. Interleukin-24 (IL-24), a cytokine-tumor suppressor, shows broad-spectrum and tumor-specific antitumor properties, and studies have demonstrated that IL-24 could conspicuously restore the chemosensitivity of MDR cancer cells. Herein, we developed a human MDR gastric cancer cell subline, SGC7901/ CDDP, by repeated selection of resistant clones of parental sensitive cells, and further investigated the chemosensitizing effects and the underlying mechanisms of adenovirus-medi- IntroductionGastric cancer is the fourth leading cause of cancer-related death in the world (1). To date, chemotherapy is the most frequently used fundamental treatment for gastric cancer. However, the main barrier to successful chemotherapy is MDR caused by insensitivity to multiple chemotherapeutic agents after exposure to a single chemotherapeutic drug (2). For decades, the most representative consensus is the overexpression of drug efflux pumps (such as P-gp) occupying a critical position in development of MDR. Consequently, several innovative chemosensitizers against P-gp, such as verapamil, trifluoperazine and cyclosporine, have been found to enhance chemosensitivity of MDR phenotype cancer cells (3). However, the clinical application of these chemosensitizers showed disappointing results (4,5), indicating that there are some unknown molecules and mechanisms also responsible for MDR. Recent studies have verified that some novel factors including defective apoptosis pathway, enhanced DNA repair activity, or altered metabolism of drugs play a critical role in promoting formation of MDR (6). Though the underlying mechanisms have been deeply studied in vitro and in vivo (6-9), the precise mechanisms involved in MDR have not been Abbreviations: MDR, multidrug resistance; P-gp, P-glycoprotein;RT-PCR, reverse transcriptase polymerase chain reaction; IC 50 , 50% inhibitory concentration

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Enhancement of 5-fluorouracil-induced cytotoxicity by leucovorin in 5-fluorouracil-resistant gastric cancer cells with upregulated expression of thymidylate synthase

Cited by 31 publications

References 34 publications

Gambogic acid potentiates the chemosensitivity of colorectal cancer cells to 5-fluorouracil by inhibiting proliferation and inducing apoptosis

Gambogic acid potentiates the chemosensitivity of colorectal cancer cells to 5-fluorouracil by inhibiting proliferation and inducing apoptosis

Establishment of a 5-fluorouracil-resistant triple-negative breast cancer cell line

Adenovirus-mediated IL-24 expression enhances the chemosensitivity of multidrug-resistant gastric cancer cells to cisplatin

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