• Asian Pacific Journal of Cancer Prevention
• /
• 제13권6호
• /
• pp.2979-2984
• /
• 2012

Recent studies have indicated a link between levels of cyclooxygenase-2 (COX-2) and development of the multidrug resistance (MDR) phenotype. The ATP-binding cassette sub-family G member 2 (ABCG2) is a major MDR-related transporter protein that is frequently overexpressed in cancer patients. In this study, we aimed to evaluate any positive correlation between COX-2 and ABCG2 gene expression using the COX-2 inducer 12-O-tetradecanoylphorbol-13-acetate (TPA) in human breast cancer cell lines. ABCG2 mRNA and protein expression was studied using real-time RT-PCR and flow cytometry, respectively. A significant increase of COX-2 mRNA expression (up to 11-fold by 4 h) was induced by TPA in MDA-MB-231 cells, this induction effect being lower in MCF-7 cells. TPA caused a considerable increase up to 9-fold in ABCG2 mRNA expression in parental MCF-7 cells, while it caused a small enhancement in ABCG2 expression up to 67 % by 4 h followed by a time-dependent decrease in ABCG2 mRNA expression in MDA-MB-231 cells. TPA treatment resulted in a slight increase of ABCG2 protein expression in MCF-7 cells, while a time-dependent decrease in ABCG2 protein expression was occurred in MDA-MB-231 cells. In conclusion, based on the observed effects of TPA in MDA-Mb-231 cells, it is proposed that TPA up-regulates ABCG2 expression in the drug sensitive MCF-7 breast cancer cell line through COX-2 unrelated pathways.

• Genomics & Informatics
• /
• 제12권4호
• /
• pp.231-235
• /
• 2014

Elevated serum uric acid levels are associated with a variety of adverse health outcomes, including gout, hypertension, diabetes mellitus, metabolic syndrome, and cardiovascular diseases. Several genome-wide association studies on uric acid levels have implicated the ATP-binding cassette, subfamily G, member 2 (ABCG2) gene as being possibly causal. We investigated an association between the single-nucleotide polymorphism (SNP) rs2725220 in the ABCG2 gene and uric acid levels in the Korean population. A total of 991 subjects in Seoul City were used for a replication study with ABCG2 SNP rs2725220. The rs2725220 SNP in the ABCG2 gene was associated with mean uric acid levels (effect per allele 0.25 mg/dL, p < 0.0001). Subjects with the GC/CC genotype had a 1.78-fold (range, 1.22- to 2.62-fold) higher risk of having abnormal uric acid levels (${\geq}7.0mg/dL$) than subjects with the GG genotype. When analyzed by gender, the association with ABCG2 was stronger in men than in women. The association with ABCG2 was much stronger in male subjects with body mass index (BMI) ${\geq}26.4$ (odds ratio, 5.09; 95% confidence interval, 2.41 to 10.8) than in male subjects with BMI < 26.4. This study clearly demonstrates that genetic variations in ABCG2 influence uric acid levels in Korean adults.

• 한국임상약학회지
• /
• 제26권1호
• /
• pp.53-58
• /
• 2016

Objective: To estimate the association between ABCG2 C421A polymorphism and response to imatinib in chronic myeloid leukemia. Methods: A systematic review was conducted to evaluate the effect of ABCG2 C421A polymorphism on imatinib response. The databases of PubMed, Embase, Web of science, CINAHL with FullText, and Cochrane Library were searched for all published studies from inception to December 2015. The following terms were used with functions of 'AND' and 'OR': 'chronic myeloid leukemia', 'CML', 'drug transporter', 'ABCG2', 'BCRP', 'polymorphisms', 'SNPs', and 'imatinib'. The studies reporting the association between ABCG2 polymorphism and imatinib response were evaluated. Results: A total of 7 studies were included in the present meta-analysis. The pooled analysis showed that ABCG2 c.421CC genotype was significantly associated with poor response to imatinib under the dominant model (CC vs CA+AA; OR: 0.56; 95% CI: 0.41, 0.77; p = 0.0004). The subgroup analysis of Asian studies demonstrated a significantly lower response in c.421CC genotype than in c.421CA or c.421AA genotype (OR: 0.52; 95% CI: 0.37, 0.73; p = 0.0002). In subgroup analyses of 5 studies, the patients with the c.421CC genotype exhibited higher risk for worse response than the patients with c.421CA or c.421AA genotype (heterozygote codominant model: CC vs. AC; OR: 0.49, 95% CI: 0.33, 0.73; p = 0.0006; homozygote codominant model: CC vs AA; OR: 0.43; 95% CI: 0.25, 0.75, p = 0.003). Conclusion: The ABCG2 c.421CC genotype was significantly associated with poor response to imatinib compared to the c.421CA and c.421AA genotypes in chronic myeloid leukemia, especially in Asian patients.

• 생명과학회지
• /
• 제26권7호
• /
• pp.835-846
• /
• 2016

항암제 내성은 화학적 치료법의 가장 큰 난관의 하나로 효과적인 항암치료를 위해서 반드시 극복 되야 할 문제이다. ABCG2는 다약제 내성과 이를 특징으로 하는 암 줄기세포와의 연관성도 매우 높다고 보고되고 있다. 최근 암용해 바이러스가 다양한 암종과 항암제내성을 보이는 암 치료에 새로운 대안으로 대두되고 있다. 이에 본 연구에서는 항암제 내성 암 치료를 위해 새로운 암용해 백시니아 바이러스 SLJ-496을 개발하였다. 본 연구에서, cytophathic effect, plaque assay, viability assay를 통하여 야생형 바이러스에 비교하여 증가된 종양친화성을 확인하였다. 또한, invitro 환경에서 대장암 세포주(HT-29, HCT-116, HCT-8)를 비롯하여 위암 세포주(AGS, NCI-N87, MKN-28), 간암 세포주(SNU-449, SNU-423, SNU-475, HepG2) 그리고 난치성 암 종인 중피 세포종(NCI-H226, NCI-H28, MSTO-211h)에서 유의적인 세포독성효능을 입증하였다. ABCG2의 발현이 높은 HT-29세포의 3차원 구형배양을 통하여 ABCG2와 암줄기세포 특성의 연관성을 증명하였으며, 항암제 내성세포 모델에서 SLJ-496GFP가 유의한 세포독성을 나타내며 암세포내 복제능을 가지는 것을 입증하였다. ABCG2를 과발현 시킨 세포주 내 야생형 바이러스에 비교하여 유의적으로 낮은 세포 생존율을 증명하였으며, 바이러스의 복제능 또한 검증하였다. 또한, 지속적인 항암제 투여를 통하여 ABCG2의 발현이 높은 항암제 내성 세포주에서의 항종양 효능 또한 입증하였다. 이상의 결과를 토대로 ABCG2가 과발현 된 암 줄기세포 및 항암제 내성에 새로운 항종양 바이러스 SLJ-496 백시니아 바이러스 치료법이 새로운 치료 대안이 될 수 있을 것이라 제안한다.

• BMB Reports
• /
• 제46권6호
• /
• pp.322-327
• /
• 2013

The ATP-binding cassette transporters ABCG5 and ABCG8 form heterodimers that limit absorption of dietary sterols in the intestine and promote cholesterol elimination from the body through hepatobiliary secretion. To identify cis-regulatory elements of the two genes, we have cloned and analyzed twenty-three evolutionary conserved region (ECR) fragments using the CMV-luciferase reporter system in HepG2 cells. Two ECRs were found to be responsive to the Liver-X-Receptor (LXR). Through elaborate deletion studies, regions containing putative LXREs were identified and the binding of $LXR{\alpha}$ was demonstrated by EMSA and ChIP assay. When the LXREs were inserted upstream of the intergenic promoter, synergistic activation by $LXR{\alpha}/RXR{\alpha}$ in combination with GATA4, $HNF4{\alpha}$, and LRH-1, which had been shown to bind to the intergenic region, was observed. In conclusion, we have identified two LXREs in ABCG5/ABCG8 genes for the first time and propose that these LXREs, especially in the ECR20, play major roles in regulating these genes.

• BMB Reports
• /
• 제51권2호
• /
• pp.98-103
• /
• 2018

Recurrence is a serious problem in patients with bladder cancer. The hypothesis for recurrence was that the proliferation of drug-resistant cells was reported, and this study focused on drug resistance due to drug efflux. Previous studies have identified FOXM1 as the key gene for recurrence. We found that FOXM1 inhibition decreased drug efflux activity and increased sensitivity to Doxorubicin. Therefore, we examined whether the expression of ABC transporter gene related to drug efflux is regulated by FOXM1. As a result, ABCG2, one of the genes involved in drug efflux, has been identified as a new target for FOXM1. We also demonstrated direct transcriptional regulation of ABCG2 by FOXM1 using ChIP assay. Consequently, in the presence of the drug, FOXM1 is proposed to directly activate ABCG2 to increase the drug efflux activation and drug resistance, thereby involving chemoresistance of bladder cancer cells. Therefore, we suggest that FOXM1 and ABCG2 may be useful targets and important parameters in the treatment of bladder cancer.

• The Korean Journal of Physiology and Pharmacology
• /
• 제16권1호
• /
• pp.11-16
• /
• 2012

Cancer stem cells (CSCs) are often characterized by the elevated expression of drug-resistance related stem-cell surface markers, such as CD133 and ABCG2. Recently, we reported that CSCs have a high level of expression of the IL-6 receptor (IL-6R). The purpose of this study was to investigate the effect of anticancer drugs on the expression of the drug resistance-related cancer stem cell markers, ABCG2, IL-6R, and CD133 in non-small cell lung cancer (NSCLC) cell lines. A549, H460, and H23 NSCLC cell lines were treated with the anticancer drugs 5-fluorouracil (5-FU; $25{\mu}g/ml$) and methotrexate (MTX; $50{\mu}g/ml$), and the expression of putative CSC markers was analyzed by fluorescent activated cell sorter (FACS) and the gene expression level of abcg2, il-6r and cd133 by reverse transcriptase-polymerase chain reaction (RT-PCR). We found that the fraction of ABCG2-positive(+) cells was significantly increased by treatment with both 5-FU and MTX in NSCLC cells, and the elevation of abcg2, il-6r and cd133 expressions in response to these drugs was also confirmed using RT-PCR. Also, the number of IL-6R(+) cells was increased by MTX in the 3 cell lines mentioned and increased by 5-FU in the H460 cell line. The number of CD133(+) cells was also significantly increased by both 5-FU and MTX treatment in all of the cell lines tested. These results indicate that 5-FU and MTX considerably enhance the expression of drug-resistance related CSC markers in NSCLC cell lines. Thus, we suggest that antimetabolite cancer drugs, such as 5-FU and MTX, can lead to the propagation of CSCs through altering the expression of CSC markers.

• Asian Pacific Journal of Cancer Prevention
• /
• 제17권4호
• /
• pp.2271-2275
• /
• 2016

Background: The value of 5-aminolevulinic acid (ALA) in fluorescence detection of peritoneal metastases and the underlying mechanisms were evaluated in patients with peritoneal surface malignancies. Materials and Methods: Oral 5-ALA was administered at a concentration of 20 mg/kg body weight with 50 ml of water 2 hours prior to surgery (n=115). The diagnostic value of 5-ALA based fluorescence production was evaluated following white light inspection during prior to cytoreductive surgery and hyperthermic intraperitoneal chemotherapy. Then, peptide transporter PEPT1 (ALA influx transporter) and ATP-binding cassette transporter ABCG2 (porphyrin efflux transporter) gene expression was determined with quantitative real time (qRT)-PCR and pathological diagnoses confirmed for all tissue samples. Results: The 5-ALA based photodynamic detection rate was 17% for appendiceal mucinous neoplasms, 54% for colorectal cancers, 33% for gastric cancers, 67% for diffuse malign peritoneal mesotheliomas, and 89% for epithelial ovarian cancer of peritoneal metastases. 5-ALA was detected in all cases of peritoneal metastases originating from cholangiocarcinomas whereas it was not able to detect any in granulosa cell and gastrointestinal stromal tumor cases. Furthermore, PEPT1 was overexpressed whereas ABCG2 expression was downregulated in tumors detected with fluorescence. Conclusions: 5-ALA provided 100% specificity and high sensitivity to detect peritoneal metastases in subgroups of patients with peritoneal surface mailgnancies. ALA influx transporter PEPT1 and porphyrin efflux transporter ABCG2 genes are important in tumor specific 5-ALA induced fluorescence in vivo. Further studies should clarify diagnostic utility of 5-ALA in peritoneal surface malignancies.

• Asian Pacific Journal of Cancer Prevention
• /
• 제14권12호
• /
• pp.7179-7186
• /
• 2013

Background and Aims: Scutellaria is one of the most popular traditional Chinese herbal remedies against various human diseases, including cancer. In this study, we examined the active effects of Scutellaria extract and its main flavonoid constituents on the proportion of side population cells within human multiple myeloma cell line RPMI8226 in vitro and explored the potential molecular mechanisms involved. Materials and Methods: The contents of flavonoids in ethanolic extract of Scutellaria baicalensis Georgi were determined using high performance liquid chromatography. The antiproliferative effect of the ethanolic extract on RPMI-8226 was determined by CCK assay. Apoptosis was measured by annexin combining with propidium iodide in a flow cytometer. Cell cycle analysis was performed by propidium iodide staining in combination with flow cytometry analysis. Hoechst 33342 exclusion assay was used for the identification of side population within RPMI8226 cells. The expression of ABCG2 protein was assessed by Western blotting assay. Results: The content of major flavonoids constitutents of Scutellaria extract was baicalin (10.2%), wogonoside (2.50%), baicalein (2.29%), and wogonin (0.99%), respectively. The crude Scutellaria extract did not show significant anti-proliferative effect, apoptosis induction and cell cycle arrest in RPMI-8226 within the concentrations of $1-75{\mu}g/mL$. However, the ethanolic extract, baicalein, wogonin and baicalin reduced the side population cells in RPMI-8226, and data showed that baicalein and wogonin had stronger inhibitory effects. Correspondingly, they also exhibited significant effects on decreasing the expression level of ABCG2 protein in RPMI-8226 in vitro. Conclusions: Our results for the first time demonstrated a novel mechanism of action for Scutellaria extract and its main active flavonoids, namely targeting SP cells by modulating the expression of ABCG2 protein. This study provides an insight for new therapeutic strategies targeting cancer stem cells of multiple myeloma.

• 대한임상검사과학회지
• /
• 제51권4호
• /
• pp.514-520
• /
• 2019

본 연구는 와송 유기용매 추출물중 DCM층을 이용하여 지방세포로 유도된 3T3-L1세포에 대한 지질대사 개선효과를 확인하는 연구이다. 세포독성을 확인하기 위하여 MTS-assay를 이용하여 6가지 분획의 와송 유기용매 추출물(EtOH, Hexane, DCM, EToAc, BuOH, H₂O)에 대한 독성검사를 실시하여 세포에 대한 안정성을 확인하였다. 그 결과 DCM추출물이 전 농도에 걸쳐 안정성이 있음을 확인하고, 지질대사 개선효과를 확인하기 위하여 DCM층을 사용하였다. 우선 지질대사 개선효과를 확인하기 위하여 지질 배출능을 측정하였다. 지방세포로 유도된 3T3-L1세포에 대하여 DCM추출물을 처리한 후 oil-red O염색을 실시하여 지질 축적량을 평가한 결과 지질 배출능이 개선된 것을 확인할 수 있었다. 또한 지질 배출능 분석을 위하여 지질수송 단백질인 ABCA1, ABCG1의 mRNA발현을 real-time PCR로 확인한 결과 DCM추출물 처리 시 유의적인 발현 증가가 나타났음을 확인 하였다. 따라서 본 연구를 통하여 와송 DCM추출물이 3T3-L1 지방세포에 대하여 지질대사 개선효과가 있음을 확인하였다.