LY294002 may overcome 5-FU resistance via down-regulation of activated p-AKT in Epstein-Barr virus-positive gastric cancer cells

Shin, Jung-Young; Kim, Jeong-Oh; Lee, Suk Kyeong; Chae, Hiun-Suk; Kang, Jin‐Hyoung

doi:10.1186/1471-2407-10-425

Cited by 68 publications

(52 citation statements)

References 28 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Activation of p53 can lead to cell cycle arrest, DNA repair, or apoptosis. Generally, phosphorylation of p53 is increased by DNA damage due to 5-FU (22)(23)(24)(25). level of p53 was increased by 5-FU in MDA-MB-231, but not in its 5-FU-resistant counterpart (Fig.…”

Section: Cross-resistance Profiles Of Mda-mb-231/5-fu Cellsmentioning

confidence: 89%

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

Takahashi

Tanaka

Inagaki

et al. 2013

International Journal of Oncology

View full text Add to dashboard Cite

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.

show abstract

Section: Cross-resistance Profiles Of Mda-mb-231/5-fu Cellsmentioning

confidence: 89%

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

Takahashi

Tanaka

Inagaki

et al. 2013

International Journal of Oncology

View full text Add to dashboard Cite

show abstract

“…As is well known, p-Akt, EGFR and Bcl-2 apoptosis-associated protein activation is one of the mechanisms of TMZ resistance (14,17). Previous studies have shown that LY294002, which suppresses PI3K, can inhibit the expression of p-Akt in cancer (18)(19)(20). Our aim was to ascertain whether LY294002 increases the cytotoxicity of TMZ in vitro.…”

Section: Introductionmentioning

confidence: 99%

LY294002 enhances cytotoxicity of temozolomide in glioma by down-regulation of the PI3K/Akt pathway

et al. 2011

View full text Add to dashboard Cite

Abstract. The introduction of temozolomide (TMZ) has advanced chemotherapy for malignant gliomas. However, a considerable number of glioblastoma (GBM) cases are refractory to TMZ. Previous studies have revealed that the PI3K/ Akt pathway is activated in an ataxia telangiectasia and Rad3 related-dependent manner in response to TMZ. Thus, we hypothesized that PI3K inhibitors may act as antitumor agents against gliomas and potentiate the cytotoxicity of TMZ. The cytotoxicity of a PI3K inhibitor, LY294002, was examined both alone and in combination with TMZ in human glioma cell lines. Proliferation of tumor cells treated with LY294002 in combination with TMZ was significantly suppressed compared to treatment with either drug used alone. The combination treatment induced a higher apoptosis rate, while reducing the invasive capability of U87 cells. The apoptosis-associated proteins, cleaved-caspase-3 and Bax, were more significantly up-regulated by the combined treatment than by TMZ used alone. In addition, p-Akt and Bcl-2, which can promote TMZ resistance, were markedly decreased by LY294002. These findings suggest that LY294002 enhances the cytotoxicity of TMZ by down-regulation of the PI3K/Akt pathway.

show abstract

“…Furthermore, the Akt/NF-κB signaling pathway serves a key role in regulating cell growth, survival and chemoresistance in ovarian and gastric cancer cells (17,18). Akt and NF-κB are involved in ovarian cancer chemoresistance through the upregulation of FLICE-inhibitory protein, XIAP, Bcl-2 and survivin (16).…”

mentioning

confidence: 99%

Hsp90 inhibitor SY-016 induces G2/M arrest and apoptosis in paclitaxel-resistant human ovarian cancer cells

et al. 2017

View full text Add to dashboard Cite

Abstract. The aim of the present study was to evaluate the in vitro effect of a heat shock protein (Hsp)90 inhibitor, SY-016, on the paclitaxel (PTX)-resistant human ovarian cancer cell line OVCAR-3PTX, and explore its mechanism of apoptosis. In the present study, SY-016 was used in combination with PTX to determine its effect on the cell proliferation and apoptosis of OVCAR-3PTX cells. The drug-resistant tumor cells were established in vitro by stepwise sequential exposure to increasing concentrations of PTX. The cell viability and cell cycle distribution were measured by MTT assay and flow cytometric analysis, respectively. The induction of apoptosis was measured by caspase-3 activity, DNA fragmentation and western blot analyses. The cell viability significantly decreased following treatment with PTX and SY-016 as compared with either drug alone. The DNA fragmentation assay revealed an induction of apoptosis. The results from the flow cytometric analysis revealed an increase in the percentage of cells in the G2/M phase. Downregulation of B-cell lymphoma (Bcl)-2, X-linked inhibitor of apoptosis protein, survivin, Akt, nuclear factor-κB and cyclin-dependent kinase 4, as well as upregulation of Bcl-2-associated X protein, were observed. SY-016 may contribute to the induction of apoptosis in OVCAR-3PTX cells. These results suggest that SY-016 in combination with PTX may be a beneficial chemotherapeutic strategy, particularly in patients with tumors refractory to PTX.

show abstract

LY294002 may overcome 5-FU resistance via down-regulation of activated p-AKT in Epstein-Barr virus-positive gastric cancer cells

Cited by 68 publications

References 28 publications

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

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

LY294002 enhances cytotoxicity of temozolomide in glioma by down-regulation of the PI3K/Akt pathway

Hsp90 inhibitor SY-016 induces G2/M arrest and apoptosis in paclitaxel-resistant human ovarian cancer cells

Contact Info

Product

Resources

About