ABC Transporters: Regulation and Association with Multidrug Resistance in Hepatocellular Carcinoma and Colorectal Carcinoma

2019 ◽  
Vol 26 (7) ◽  
pp. 1224-1250 ◽  
Author(s):  
María Paula Ceballos ◽  
Juan Pablo Rigalli ◽  
Lucila Inés Ceré ◽  
Mariana Semeniuk ◽  
Viviana Alicia Catania ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Multidrug Resistance ◽  
Colorectal Carcinoma ◽  
Cancer Cells ◽  
Abc Transporters ◽  
Cancer Resistance ◽  
Glycoprotein P ◽  
Future Directions ◽  
Associated Proteins ◽  
Post Transcriptional Regulation

:For most cancers, the treatment of choice is still chemotherapy despite its severe adverse effects, systemic toxicity and limited efficacy due to the development of multidrug resistance (MDR). MDR leads to chemotherapy failure generally associated with a decrease in drug concentration inside cancer cells, frequently due to the overexpression of ABC transporters such as P-glycoprotein (P-gp/MDR1/ABCB1), multidrug resistance-associated proteins (MRPs/ABCCs), and breast cancer resistance protein (BCRP/ABCG2), which limits the efficacy of chemotherapeutic drugs. The aim of this review is to compile information about transcriptional and post-transcriptional regulation of ABC transporters and discuss their role in mediating MDR in cancer cells.:This review also focuses on drug resistance by ABC efflux transporters in cancer cells, particularly hepatocellular carcinoma (HCC) and colorectal carcinoma (CRC) cells. Some aspects of the chemotherapy failure and future directions to overcome this problem are also discussed.

scholarly journals The role of dietary flavonoids for modulation of ATP binding cassette transporter mediated multidrug resistance

eFood ◽  
2021 ◽  
Author(s):  
Hui Teng ◽  
Hongting Deng ◽  
Yuanju He ◽  
Qiyan Lv ◽  
Lei Chen
Keyword(s):  
Multidrug Resistance ◽  
Abc Transporters ◽  
Systemic Circulation ◽  
Atp Binding ◽  
Cancer Resistance ◽  
Associated Proteins ◽  
Food Toxin ◽  
Atp Binding Cassette

Flavonoids are widely existing compounds with enormous pharmacological effects from food and medicine. However, the low bioavailability in intestinal absorption and metabolism limits their clinical application. Intestinal efflux ABC (ATP binding cassette) transporters, including P-glycoprotein (P-gp), breast cancer resistance protein (BCRP) and multidrug resistance-associated proteins (MRPs), act as "pumping doors" to regulate the efflux of flavonoids from intestinal epithelial cells into the intestinal cavity or the systemic circulation. The present review describes the critical effect of ABC transporters involved in the efflux of flavonoids which depend on its efflux direction. And the role of flavonoids for modulation of intestinal ABC transporters was emphasized and several examples were given. We summarized that the resistance effect of flavonoid-mediated multidrug on ABC transporters may influence the bioavailability of drugs, bioactive ingredients and/or toxic compounds upon dietary uptake. Meanwhile, flavonoids functionalized as reversing agents of the ABC transporter may be an important mechanism for unexpected food-drug, food-toxin or food-food interactions. The overview also indicates that elucidation of the action and mechanism of the intestinal metabolic enzymes-efflux transporters coupling will lay a foundation for improving the bioavailability of flavonoids <i>in vivo</i> and increasing their clinical efficacy.

Role of ATP-binding Cassette Transporters in Sorafenib Therapy for Hepatocellular Carcinoma: an overview

2021 ◽  
Vol 22 ◽  
Author(s):  
Maria Manuela Estevinho ◽  
Carlos Fernandes ◽  
João Carlos Silva ◽  
Ana Catarina Gomes ◽  
Edgar Afecto ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Multidrug Resistance ◽  
Abc Transporters ◽  
Current Knowledge ◽  
Molecular Therapy ◽  
Resistance Factors ◽  
Sorafenib Therapy ◽  
Online Databases ◽  
Associated Proteins

Background: Molecular therapy with sorafenib remains the mainstay for advanced-stage hepatocellular carcinoma. Notwithstanding, treatment efficacy is low, with few patients obtaining long-lasting benefits due to the high chemoresistance rate. Objective: To perform, for the first time, an overview of the literature concerning the role of adenosine triphosphate-binding cassette (ABC) transporters in sorafenib therapy for hepatocellular carcinoma. Methods: Three online databases (PubMed, Web of Science and Scopus) were searched, from inception to October 2020. Studies selection, analysis and data collection was independently performed by two authors. Results: The search yielded 224 results; 29 were selected for inclusion. Most studies were pre-clinical, using HCC cell lines; three used human samples. Studies highlight the effect of sorafenib in decreasing ABC transporters expression. Conversely, it is described the role of ABC transporters, particularly multidrug resistance protein 1 (MDR-1), multidrug resistance-associated proteins 1 and 2 (MRP-1 and MRP-2) and ABC subfamily G member 2 (ABCG2) in sorafenib pharmacokinetics and pharmacodynamics, being key resistance factors. Combination therapy with naturally available or synthetic compounds that modulate ABC transporters may revert sorafenib resistance, by increasing absorption and intracellular concentration. Conclusion: A deeper understanding of ABC transporters’ mechanisms may provide guidance for developing innovative approaches for hepatocellular carcinoma. Further studies are warranted to translate the current knowledge into practice and paving the way to individualized therapy.

ABC Transporters in Extrahepatic Tissues: Pharmacological Regulation in Heart and Intestine

2019 ◽  
Vol 26 (7) ◽  
pp. 1155-1184 ◽  
Author(s):  
Silvina Villanueva ◽  
Wei Zhang ◽  
Felipe Zecchinati ◽  
Aldo Mottino ◽  
Mary Vore
Keyword(s):  
Small Intestine ◽  
Abc Transporters ◽  
Reproductive Organs ◽  
The Body ◽  
Cancer Resistance ◽  
Glycoprotein P ◽  
Abc Proteins ◽  
Therapeutic Drugs ◽  
Associated Proteins ◽  
Extrahepatic Tissues

ATP binding cassette (ABC) transporters are transmembrane proteins expressed in secretory epithelia like the liver, kidneys and intestine, in the epithelia exhibiting barrier function such as the blood-brain barrier and placenta, and to a much lesser extent, in tissues like reproductive organs, lungs, heart and pancreas, among others. They regulate internal distribution of endogenous metabolites and xenobiotics including drugs of therapeutic use and also participate in their elimination from the body. We here describe the function and regulation of ABC transporters in the heart and small intestine, as examples of extrahepatic tissues, in which ABC proteins play clearly different roles. In the heart, they are involved in tissue pathogenesis as well as in protecting this organ against toxic compounds and druginduced oxidative stress. The small intestine is highly exposed to therapeutic drugs taken orally and, consequently, ABC transporters localized on its surface strongly influence drug absorption and pharmacokinetics. Examples of the ABC proteins currently described are Multidrug Resistance-associated Proteins 1 and 2 (MRP1 and 2) for heart and small intestine, respectively, and P-glycoprotein (P-gp) and Breast Cancer Resistance Protein (BCRP) for both organs.

scholarly journals MiR-331-3p Links to Drug Resistance of Pancreatic Cancer Cells by Activating WNT/β-Catenin Signal via ST7L

2020 ◽  
Vol 19 ◽  
pp. 153303382094580
Author(s):  
Ting Zhan ◽  
Xiaoli Chen ◽  
Xia Tian ◽  
Zheng Han ◽  
Meng Liu ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Drug Resistance ◽  
Multidrug Resistance ◽  
Cancer Cells ◽  
Breast Cancer Resistance Protein ◽  
Cancer Resistance ◽  
Multidrug Resistance Protein 1 ◽  
Pancreatic Cancer Cells ◽  
Resistance Protein ◽  
Multidrug Resistance Related Protein

Background: Pancreatic cancer is an aggressive type of cancer with poor prognosis, short survival rate, and high mortality. Drug resistance is a major cause of treatment failure in the disease. MiR-331-3p has been reported to play an important role in several cancers. We previously showed that miR-331-3p is upregulated in pancreatic cancer and promotes pancreatic cancer cell proliferation and epithelial-to-mesenchymal transition–mediated metastasis by targeting ST7L. However, it is uncertain whether miR-331-3p is involved in drug resistance. Methods: We investigated the relationship between miR-331-3p and pancreatic cancer drug resistance. As part of this, microRNA mimics or inhibitors were transfected into pancreatic cancer cells. Quantitative polymerase chain reaction was used to detect miR-331-3p expression, and flow cytometry was used to detect cell apoptosis. The Cell Counting Kit-8 assay was used to measure the IC50 values of gemcitabine in pancreatic cancer cells. The expression of multidrug resistance protein 1, multidrug resistance-related protein 1, breast cancer resistance protein, β-Catenin, c-Myc, Cyclin D1, Bcl-2, and Caspase-3 was evaluated by Western blotting. Results: We confirmed that miR-331-3p is upregulated in gemcitabine-treated pancreatic cancer cells and plasma from chemotherapy patients. We also confirmed that miR-331-3p inhibition decreased drug resistance by regulating cell apoptosis and multidrug resistance protein 1, multidrug resistance-related protein 1, and breast cancer resistance protein expression in pancreatic cancer cells, whereas miR-331-3p overexpression had the opposite effect. We further demonstrated that miR-331-3p effects in drug resistance were partially reversed by ST7L overexpression. In addition, overexpression of miR-331-3p activated Wnt/β-catenin signaling in pancreatic cancer cells, and ST7L overexpression restored activation of Wnt/β-catenin signaling. Conclusions: Taken together, our data demonstrate that miR-331-3p contributes to drug resistance by activating Wnt/β-catenin signaling via ST7L in pancreatic cancer cells. These data provide a theoretical basis for new targeted therapies in the future.

DJ-1 is involved in the multidrug resistance of SGC7901 gastric cancer cells through PTEN/PI3K/Akt/Nrf2 pathway

2020 ◽  
Vol 52 (11) ◽  
pp. 1202-1214
Author(s):  
Lejia Qiu ◽  
Zhaoxia Ma ◽  
Xiaoran Li ◽  
Yizhang Deng ◽  
Guangling Duan ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Multidrug Resistance ◽  
Cancer Cells ◽  
Gastric Cancer Cells ◽  
Glycoprotein P ◽  
Nrf2 Pathway ◽  
P Glycoprotein ◽  
New Findings ◽  
Nrf2 Signaling Pathway ◽  
Common Malignancy

Abstract Gastric cancer is a common malignancy worldwide. The occurrence of multidrug resistance (MDR) is the major obstacle for effective gastric cancer chemotherapy. In this study, the in-depth molecular mechanism of the DJ-1-induced MDR in SGC7901 gastric cancer cells was investigated. The results showed that DJ-1 expression level was higher in MDR variant SGC7901/VCR cells than that in its parental SGC7901 cells. Moreover, DJ-1 overexpression conferred the MDR phenotype to SGC7901 cells, while DJ-1 knockdown in SGC7901/VCR cells induced re-sensitization to adriamycin, vincristine, cisplatin, and 5-fluorouracil. These results suggested that DJ-1 mediated the development of MDR in SGC7901 gastric cancer cells. Importantly, further data revealed that the activation of PI3k/Akt and Nrf2 signaling pathway were required for the DJ-1-induced MDR phenotype in SGC7901 gastric cancer cells. Meanwhile, we found that PI3k/Akt pathway was activated probably through DJ-1 directly binding to and negatively regulating PTEN, consequently resulting in Nrf2 phosphorylation and activation, and thereby inducing Nrf2-dependent P-glycoprotein (P-gp) and Bcl-2 expressions in the DJ-1-mediated MDR of SGC7901 gastric cancer cells. Overall, these results revealed that activating PTEN/PI3K/Akt/Nrf2 pathway and subsequently upregulating P-gp and Bcl-2 expression could be a critical mechanism by which DJ-1 mediates the development of MDR in SGC7901 gastric cancer cells. The new findings may be helpful for understanding the mechanisms of MDR in gastric cancer cells, prompting its further investigation as a molecular target to overcome MDR.

scholarly journals Chorioamnionitis Induces a Specific Signature of Placental ABC Transporters Associated with an Increase of miR-331-5p in the Human Preterm Placenta

2018 ◽  
Vol 45 (2) ◽  
pp. 591-604 ◽  
Author(s):  
Guinever Eustaquio do Imperio ◽  
Enrrico Bloise ◽  
Mohsen Javam ◽  
Phetcharawan Lye ◽  
Andrea Constantinof ◽  
...  
Keyword(s):  
Abc Transporter ◽  
Abc Transporters ◽  
Staining Intensity ◽  
Distinct Pattern ◽  
Mrna Levels ◽  
Cancer Resistance ◽  
Glycoprotein P ◽  
Immunological Responses

Background/Aims: The ATP-binding cassette (ABC) transporters mediate drug biodisposition and immunological responses in the placental barrier. In vitro infective challenges alter expression of specific placental ABC transporters. We hypothesized that chorioamnionitis induces a distinct pattern of ABC transporter expression. Methods: Gene expression of 50 ABC transporters was assessed using TaqMan® Human ABC Transporter Array, in preterm human placentas without (PTD; n=6) or with histological chorioamnionitis (PTDC; n=6). Validation was performed using qPCR, immunohistochemistry and Western blot. MicroRNAs known to regulate P-glycoprotein (P-gp) were examined by qPCR. Results: Up-regulation of ABCB9, ABCC2 and ABCF2 mRNA was detected in chorioamnionitis (p<0.05), whereas placental ABCB1 (P-gp; p=0.051) and ABCG2 (breast cancer resistance protein-BCRP) mRNA levels (p=0.055) approached near significant up-regulation. In most cases, the magnitude of the effect significantly correlated to the severity of inflammation. Upon validation, increased placental ABCB1 and ABCG2 mRNA levels (p<0.05) were observed. At the level of immunohistochemistry, while BCRP was increased (p<0.05), P-gp staining intensity was significantly decreased (p<0.05) in PTDC. miR-331-5p, involved in P-gp suppression, was upregulated in PTDC (p<0.01) and correlated to the grade of chorioamnionitis (p<0.01). Conclusions: Alterations in the expression of ABC transporters will likely lead to modified transport of clinically relevant compounds at the inflamed placenta. A better understanding of the potential role of these transporters in the events surrounding PTD may also enable new strategies to be developed for prevention and treatment of PTD.

scholarly journals Multidrug resistance-associated ABC transporters – too much of one thing, good for nothing

2012 ◽  
Vol 3 (4) ◽  
pp. 319-331 ◽  
Author(s):  
Jirina Prochazkova ◽  
Martina Lanova ◽  
Jiri Pachernik
Keyword(s):  
Multidrug Resistance ◽  
Cancer Cells ◽  
Abc Transporters ◽  
Family Members ◽  
Atp Binding ◽  
Detailed Mechanism ◽  
P Glycoprotein ◽  
The Future ◽  
Good For

AbstractOverexpression of ATP-binding cassette (ABC) transporters in cancer cells results in multidrug resistance (MDR) which leads to unsuccessful chemotherapy. The most important MDR-associated members of ABC superfamily are ABC B1/P-glycoprotein/MDR1, ABC C1/multidrug resistance associated protein 1 (MRP1), and ABC G2/BCRP. This study is not only focused on function, substrates, and localization of these popular proteins but also on other ABC C family members such as ABC C2–6/MRP2-6 and ABC C7/CFTR. Current research is mainly oriented on the cancer-promoting role of these proteins, but important lessons could also be learned from the physiological roles of these proteins or from polymorphisms affecting their function. Thorough knowledge of structure and detailed mechanism of efflux can aid in the discovery of new chemotherapy targets in the future. Although the best way on how to deal with MDR would be to prevent its development, we describe some new promising strategies on how to conquer both inherited and induced MDRs.

Inhibition of Hexokinase II Inactivates ABC Transporters and Restores Drug Sensitivity in Myeloma Cells

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 135-135
Author(s):  
Ayako Nakano ◽  
Masahiro Abe ◽  
Daisuke Tsuji ◽  
Hirokazu Miki ◽  
Akishige Ikegame ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Tumor Growth ◽  
Cancer Cells ◽  
Abc Transporter ◽  
Abc Transporters ◽  
Malignant Cells ◽  
Cancer Resistance ◽  
Hexokinase Ii ◽  
Atp Production ◽  
Rpmi 8226

Abstract Abstract 135 Malignant cells aberrantly up-regulate ATP-binding cassette (ABC) transporters and ATP-dependent drug efflux pumps, which causes drug resistance. Because the activity of TCA cycle in mitochondria is suppressed through oncogenic alterations including the mutation of p53, ATP is largely produced by aerobic glycolytic metabolism enhanced in malignant cells (the Warburg effect). Hexokinase II (HKII), a key enzyme of glycolysis, is widely over-expressed in cancer cells. However, HKII levels and its roles in ATP production and ATP-dependent cellular process have not been elucidated in hematopoietic malignant cells including myeloma (MM) cells. In the present study, we therefore explored the expression levels of HKII and the effect of HKII inhibition on ABC transporter activity as well as the susceptibility to chemotherapeutic agents in MM cells. HKII protein was constitutively expressed at higher level in MM cells than in normal peripheral blood mononuclear cells (PBMCs). The expression level of HKII in MM cells was further up-regulated when cocultured with osteoclasts. 3-bromopyruvate (3BrPA), an inhibitor of HKII promptly inhibited glycolysis and substantially suppressed ATP production in MM cells but not in normal PBMCs. 3BrPA preferentially induced cell death in MM cells but not in normal hematopoietic cells in bone marrow samples from patients with MM, suggesting that HKII is a potential target for treatment of MM cells. We next examined the effects of 3BrPA on ABC transporter activity in RPMI 8226 (MM) and KG-1 (acute myeloid leukemia) cells which are aberrantly over-expressed breast cancer resistance protein (ABCG2) and P-glycoprotein (ABCB1), respectively. After passive incorporation of auto-fluorescence emitting daunorubicin, these cells were washed and incubated for 2 hours without daunorubicin in the absence or presence of 3BrPA, and then the intracellular daunorubicin levels were measured by flow cytometry. Treatment with 3BrPA markedly enhanced the accumulation and retention of daunorubicin in both cells. Therefore, inhibition of HKII by 3BrPA appears to be able to effectively deplete intracellular ATP production and suppress ABC transporter activity. Importantly, 3BrPA restored cytotoxic effects of doxorubicin and daunorubicin on RPMI 8226 and KG-1 cells. We next focused on “Side population (SP)” which is regarded as a highly drug-resistant fraction with enhanced ABC transporter activity, and contains clonogenic or tumor-initiating cells. SP cells isolated from RPMI 8226 cells exhibited higher levels of glycolysis with an increased expression of genes involved in the glycolytic pathway. Treatment with 3BrPA abolished Hoechst 33342 exclusion in the SP cells, and clonogenic capacity in RPMI 8226 and KG-1 cells. Furthermore, 3BrPA cooperatively suppressed subcutaneous tumor growth in combination with doxorubicin in RPMI 8226-implanted mice. These results demonstrate that HKII is a tumor specific target for treatment of MM and that inhibition of HKII effectively depletes ATP and inactivate ABC transporters to overcome drug resistance. ABC transporter-expressing SP cells with enhanced glycolysis and clonogenic cells with high proliferative potential are suggested to be a good target of the inhibition of glycolysis. These findings highlight a novel role of enhanced glycolysis in malignant cells in tumor growth and drug resistance, and relevance to anti-cancer strategies attempting to target unique metabolic pathway of cancer cells. Disclosures: No relevant conflicts of interest to declare.

Two novel multidrug resistance associated protein (MRP/ABCC) from the Mediterranean mussel (Mytilus galloprovincialis): characterization and expression patterns in detoxifying tissues

2015 ◽  
Vol 93 (7) ◽  
pp. 567-578 ◽  
Author(s):  
V. Lozano ◽  
R. Martínez-Escauriaza ◽  
M.L. Pérez-Parallé ◽  
A.J. Pazos ◽  
J.L. Sánchez
Keyword(s):  
Multidrug Resistance ◽  
Digestive Gland ◽  
Okadaic Acid ◽  
Abc Transporters ◽  
Mytilus Galloprovincialis ◽  
Expression Patterns ◽  
Cancer Resistance ◽  
Mediterranean Mussel ◽  
The Mediterranean

Multidrug resistance associated proteins (MRP) belong to the ABCC branch of the ABC transporters. The MRP together with P-gp (P-glycoprotein; MDR1; ABCB1) and BCRP (breast cancer resistance protein; ABCG2) confer multixenobiotic resistance (MXR) in marine vertebrates. In aquatic invertebrates, little is known about the presence and role of these ABC transporters. The ABC transporters play an important role in the absorption, distribution, and excretion of drugs, xenobiotics, and endogenous compounds and are predominantly expressed in excretory organs. In the present study, we identified and characterized two MRP/ABCC transporters (mrp1 and mrp2) from the Mediterranean mussel (Mytilus galloprovincialis Lamarck, 1819). The two cDNAs finally obtained were 4648 bp for mrp1 and 5065 bp for mrp2 with open reading frames of 1500 and 1524 residues, respectively. Analysis of the amino acid sequences revealed the structural organization of ABC transporters with the typical and highly conserved motifs. The expression levels of these genes revealed that the highest expression of mrp1 and mrp2 genes was found in the digestive gland followed by gills, and the lowest expression of the three tissues was detected in the mantle. The expression of these genes was also studied in mussels naturally contaminated with okadaic acid (from a bloom of Dinophysis acuminata Claparède and Lachmann, 1859). The overexpression of mrp2 in the digestive gland suggests that this gene is involved in the process of detoxification of okadaic acid in M. galloprovincilais. These expression patterns agree with the suggested role of these genes in the protection against endogenous or exogenous compounds in aquatic organisms.

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