Persistence of side population cells with high drug efflux capacity in pancreatic cancer

Zhou, Jing; Wang, Chunyou; Liu, Tao; Wu, Bin; Zhou, Feng; Xiong, Jianping; Wu, Heshui; Ji, Tao; Zhao, Gang; Yang, Ming; Gou, Shanmiao

doi:10.3748/wjg.14.925

Cited by 102 publications

(92 citation statements)

References 28 publications

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“…Additionally, the increased expression of ATP-binding cassette genes in gemcitabineresistant cells demonstrated that these genes may contribute to pancreatic cancer drug resistance. The ATP-binding cassette genes have been shown to be overexpressed in a subpopulation of pancreatic cancer cells with stem cell characteristics, which play an important role in oncogenesis, development and drug resistance (16)(17)(18). ABCB1, ABCC1 and ABCG2 expression were altered in a similar manner, which indicated that ATP-binding cassette genes play a joint role in oncogenesis and drug resistance.…”

Section: Discussionsupporting

confidence: 48%

Expression and promoter methylation analysis of ATP-binding cassette genes in pancreatic cancer

Chen

Xue²,

Wang³

et al. 2011

Oncol Rep

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Abstract. We investigated the relationship of ABCB1/MDR1, ABCC1/MRP1 and ABCG2/BCRP expression and promoter methylation with pancreatic cancer tumorigenesis and drug resistance. Gemcitabine-resistant pancreatic cancer cells, SW1990/ GZ (33.3-fold increased resistance), were obtained by treating SW1990 cells with gemcitabine. The expression of ABCB1/ MDR1, ABCC1/MRP1 and ABCG2/BCRP was determined by quantitative real-time RT-PCR in the cell lines, 3 normal pancreatic tissues, 15 human pancreatic cancer samples and 15 adjacent tissues. Promoter methylation was determined in cell lines by bisulfite genomic sequencing. ABCB1/MDR1, ABCC1/ MRP1 and ABCG2/BCRP were upregulated in SW1990 and SW1990/GZ compared with normal pancreatic tissue, and expression in SW1990/GZ was significantly higher than in SW1990 cells. ABCB1/MDR1, ABCC1/MRP1 and ABCG2/ BCRP were upregulated in pancreatic cancer tissues, compared to adjacent tissues. The ABCB1/MDR1, ABCC1/MRP1 and ABCG2/BCRP promoter were hypomethylated in all the cell lines. ABCB1/MDR1, ABCC1/MRP1 and ABCG2/BCRP expression correlated with pancreatic cancer tumorigenesis and drug resistance in a mechanism that is independent of promoter methylation. IntroductionPancreatic cancer is among the 10 leading causes of cancerrelated deaths, with a 5-year survival <5% (1). Most patients have advanced stage disease at diagnosis. One fifth of pancreatic cancer patients present in the early stage and are eligible for surgical resection (2), which is a complex operation that is associated with high rates of operative morbidity. Pancreatic cancer also shows resistance to chemotherapy. Gemcitabine, the standard treatment in advanced disease, prolongs survival by 5-6 months. Chemotherapy is largely ineffective for patients with metastases as disease frequently redevelops even after surgery; therefore, there is an urgent need to understand the molecular mechanism of chemoresistance in pancreatic cancer.One well-known mechanism of chemoresistance is the overexpression of energy-dependent pumps, such as adenosine triphosphate-binding cassette (ABC) transporters, which lead to the extrusion of drugs and their metabolites (3). P-gp, a 170,000-Da phosphoglycoprotein that consists of two ATP binding cassettes and two transmembrane regions, which is associated with chemoresistance in cancers of the gastrointestinal tract, liver and kidneys (4). The breast cancer resistance protein (ABCG2/BCRP) is a 655-amino-acid polypeptide transporter with a wide range of substrates associated with breast cancer resistance (5). Additionally, ABCC1/MRP1 is correlated with differentiation grade and tumor size in primary hepatocellular carcinoma and breast cancer (6,7).DNA methylation of CpG dinucleotides is the predominant epigenetic gene expression modification. More than 40% of protein coding genes have 5' CpG rich segments, termed CpG islands (8). The aberrant methylation of gene promoters is frequently observed in human cancers and correlates with carcinogenesis, tumor progression and chemosensitivity (9,10). M...

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Section: Discussionsupporting

confidence: 48%

Expression and promoter methylation analysis of ATP-binding cassette genes in pancreatic cancer

Chen

Xue²,

Wang³

et al. 2011

Oncol Rep

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“…Accordingly, in this study, we wished to establish a murine lung CSC model. Prior reports have suggested that side population (SP) cells separated from diverse cancer cells possess stem cell-like properties (Ho et al, 2007;Prince et al, 2007;Wang et al, 2007;Sung et al, 2008;Zhou et al, 2008). On the contrary, several recently published studies have shown that SP cells were not enriched for a stem-like self-renewal phenotype (Broadley et al, 2011).…”

Section: Introductionmentioning

confidence: 88%

Identification of a Cancer Stem-like Population in the Lewis Lung Cancer Cell Line

Zhang

Fan²,

Yao³

et al. 2012

Asian Pacific Journal of Cancer Prevention

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“…Several studies have shown that the resistance of pancreatic cancer cells to chemotherapeutics including gemcitabine, is the result of reduced cellular uptake via influx proteins (12) or their efficient removal from cells by efflux proteins (15,24). Synthetic antioxidants such as BHA and BHT are widely used in pharmaceutical products as well as in the food industry to protect susceptible chemicals against oxidation (27,28).…”

Section: Discussionmentioning

confidence: 99%

“…Gemcitabine is considered the "gold" standard chemotherapeutic agent for treatment of pancreatic cancer; however, the response rate to gemcitabine alone or in combination with other chemotherapeutics is only marginal (1,2,4,5). Among many reasons that have been investigated to explain this chemotherapeutic inefficiency (6)(7)(8)(9)(10)(11), reduced cellular uptake of gemcitabine as a result of down regulation of influx proteins and/or upregulation of the efflux proteins has been highlighted in several studies (12)(13)(14)(15) . The alteration of influx and efflux protein expression may lead to a significant reduction in the intracellular concentration of chemotherapeutic agents, which ultimately results in poor response to treatment and development of multiple drug resistance (MDR) against several structurally unrelated anticancer agents (13)(14)(15)(16)(17)(18).…”

Section: Introductionmentioning

confidence: 99%

“…Among many reasons that have been investigated to explain this chemotherapeutic inefficiency (6)(7)(8)(9)(10)(11), reduced cellular uptake of gemcitabine as a result of down regulation of influx proteins and/or upregulation of the efflux proteins has been highlighted in several studies (12)(13)(14)(15) . The alteration of influx and efflux protein expression may lead to a significant reduction in the intracellular concentration of chemotherapeutic agents, which ultimately results in poor response to treatment and development of multiple drug resistance (MDR) against several structurally unrelated anticancer agents (13)(14)(15)(16)(17)(18). Gemcitabine is taken up into the cells by various concentrative nucleoside transporter (CNT) and equilibrative nucleoside transporter (ENT) isoforms (19)(20)(21).…”

Section: Introductionmentioning

confidence: 99%

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Calcitriol Reverses Induced Expression of Efflux Proteins and Potentiates Cytotoxic Activity of Gemcitabine in Capan-2 Pancreatic Cancer Cells

Kohan¹,

Sani²,

Boroujerdi³

2017

J Pharm Pharm Sci

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ABSTRACT-Purpose. Efflux and influx proteins play a major role in chemo-resistance by affecting the net cellular uptake of anti-cancer drugs. Hence, alteration of the efflux and influx protein expression may result in variations of chemotherapeutics uptake and consequently cell death rate. The present study investigated the effects of pre-treatment of capan-2 pancreatic cancer cells with calcitriol, butylated hydroxytoluene (BHT), butylated hydroxyanisole (BHA) or silibinin on the induction of three major efflux proteins and the main gemcitabine influx protein. The influence of the pre-treatments on the net cellular uptake of gemcitabine, total ATPase activity, and cell death rate were also evaluated. Methods. Capan-2 pancreatic cancer cells were pre-treated for 24 h with calcitriol, BHT, BHA, or silibinin, followed by gemcitabine treatment. The concentration of gemcitabine was quantified using ultra-performance liquid chromatography (UPLC). Real-time polymerase chain reaction (RT-PCR) was utilized in order to investigate the expression of the mRNAs. The expression of the proteins was assessed using western blotting. Measurement of the ATPase activity was conducted utilizing a colorimetric method and viability of the cells was determined using a luminescent cell viability assay. Results. Protein expression studies showed that BHT, silibinin, and BHA increased expression of the efflux proteins and decreased the overall uptake of gemcitabine, whereas calcitriol significantly inhibited expression of the efflux proteins and increased gemcitabine uptake. Expression of specific mRNAs correlated reasonably well with the levels of corresponding proteins. Additionally, the expression of efflux proteins and ATPase activity were well correlated, signifying that the induced efflux proteins are functionally active. Moreover, pre-treatment with calcitriol resulted in a significant increase in cell death with gemcitabine treatment, whereas, BHA significantly reduced the cell death rate. On the other hand, pre-treatment with BHT and silibinin had no significant effect on the cell death rate. Conclusions. Pre-treatment of the pancreatic cancer cells with calcitriol significantly increased gemcitabine cellular uptake and consequently decreased cell viability after treatment with gemcitabine, whereas BHA significantly reduced gemcitabine uptake and decreased cell death rate, which were at least partially attributed to the alteration of expression of efflux and influx proteins.

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Persistence of side population cells with high drug efflux capacity in pancreatic cancer

Cited by 102 publications

References 28 publications

Expression and promoter methylation analysis of ATP-binding cassette genes in pancreatic cancer

Expression and promoter methylation analysis of ATP-binding cassette genes in pancreatic cancer

Identification of a Cancer Stem-like Population in the Lewis Lung Cancer Cell Line

Calcitriol Reverses Induced Expression of Efflux Proteins and Potentiates Cytotoxic Activity of Gemcitabine in Capan-2 Pancreatic Cancer Cells

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