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

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.

Download Full-text

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

eFood ◽

10.53365/efood.k/144604 ◽

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.

Download Full-text

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

Current Medicinal Chemistry ◽

10.2174/0929867325666180105103637 ◽

2019 ◽

Vol 26 (7) ◽

pp. 1224-1250 ◽

Cited By ~ 20

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.

Download Full-text

Towards unravelling the role of the lipid droplet-associated proteins perilipin, adipophilin, and TIP47 in hepatocellular carcinoma

Zeitschrift für Gastroenterologie ◽

10.1055/s-0029-1191848 ◽

2009 ◽

Vol 47 (01) ◽

Author(s):

BK Straub ◽

S Singer ◽

J Lehmann-Koch ◽

H Heid ◽

E Specht ◽

...

Keyword(s):

Hepatocellular Carcinoma ◽

Lipid Droplet ◽

Associated Proteins

Download Full-text

Multiple Roles of Autophagy in the Sorafenib Resistance of Hepatocellular Carcinoma

Cellular Physiology and Biochemistry ◽

10.1159/000485285 ◽

2017 ◽

Vol 44 (2) ◽

pp. 716-727 ◽

Cited By ~ 40

Author(s):

Ting Sun ◽

Hongchun Liu ◽

Liang Ming

Keyword(s):

Hepatocellular Carcinoma ◽

Current Knowledge ◽

Acquired Resistance ◽

Multiple Roles ◽

Multikinase Inhibitor ◽

Advanced Hcc ◽

Cellular Autophagy ◽

Advanced Stages ◽

Hcc Cells

Hepatocellular carcinoma (HCC) is the second leading cause of cancer-related death worldwide, and prognosis remains unsatisfactory since the disease is often diagnosed at the advanced stages. Currently, the multikinase inhibitor sorafenib is the only drug approved for the treatment of advanced HCC. However, primary or acquired resistance to sorafenib develops, generating a roadblock in HCC therapy. Autophagy is an intracellular lysosomal pathway involved in protein and organelle degradation, with an astonishing number of connections to human disease and physiology. Current understanding of the role of autophagy in the progression of cancer and the response to cancer therapy remains controversial. Sorafenib is able to induce autophagy in HCC, but the effect of autophagy is indistinct. Some studies established that sorafenib-induced autophagy serves as a pro-survival response. However, other studies found that sorafenib-induced autophagy improves the lethality of sorafenib against HCC cells. The mechanisms underlying autophagy and sorafenib resistance remain elusive. The purpose of this review is to summarize the progress of research focused on autophagy and sorafenib resistance and to update current knowledge of how cellular autophagy impacts sorafenib sensitivity in HCC treatment.

Download Full-text

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

BioMolecular Concepts ◽

10.1515/bmc-2012-0006 ◽

2012 ◽

Vol 3 (4) ◽

pp. 319-331 ◽

Cited By ~ 3

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.

Download Full-text

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

Canadian Journal of Zoology ◽

10.1139/cjz-2015-0011 ◽

2015 ◽

Vol 93 (7) ◽

pp. 567-578 ◽

Cited By ~ 4

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.

Download Full-text