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Modulation of Classical Multidrug Resistance and Drug Resistance in General
Published in Gertjan J. L. Kaspers, Bertrand Coiffier, Michael C. Heinrich, Elihu Estey, Innovative Leukemia and Lymphoma Therapy, 2019
In addition to P-gp, several other members of the ABC gene family also function as drug transporters (47–55). MRP1/ABCC1 confers resistance to anthracyclines, vinca alkaloids and epipodophyllotoxins, and transports glutathione conjugates of drugs (47,48,52–55). None of the other ABC transporters are as strongly associated with clinical endpoints as P-gp/MDR1, and clinical strategies for reversing resistance related to these transporters have not been developed. MRP2/ABCC2, also known as the canalicular multiple organic anion transporter (cMOAT), is highly expressed in the biliary tract, and transports glucuronide and glutathione drug conjugates, including anthracyclines. It is the gene whose deficiency results in the Dubin-Jonson syndrome (51). MRP2 is involved in hepatic excretion of anticancer drugs, but has not been implicated as a resistance factor in cancers (49,55). The MRP3/ABCC3 gene confers resistance to epipodophyllotoxins as well as to methotrexate (50,51), while MRP4/ABCC4 and MRP5/ABCC5 confer resistance to nucleotide analogues and their metabolites (51).
Regulation of Human CYP2D6
Published in Shufeng Zhou, Cytochrome P450 2D6, 2018
Alcohol abuse leads to approximately 2.5 million deaths worldwide, with cirrhosis contributing to 16.6% of reported deaths (Ferraguti et al. 2015; Whiteford et al. 2013). According to Centers for Disease Control and Prevention, approximately 15,000 Americans die every year of alcoholic liver cirrhosis (Polednak 2012). A recent study has shown that alcoholic cirrhosis significantly increases ABCC4, 5, ABCG2, and solute carrier organic anion (SLCO) 2B1 mRNA expression and decreases SLCO1B3 mRNA expression in the liver (More et al. 2013). SLCO transporters are often described as uptake transporters since they are predominantly localized to the sinusoidal membrane and typically extract chemicals from blood into hepatocytes (Hagenbuch and Meier 2004). In humans, SLCO1B1, 1B3, 2B1, and 1A2 have relatively high expression in the liver. SLCO1B1, 1B3, and 2B1 transport a diverse range of drugs, including benzylpenicillin, statins, and estradiol glucuronide (Hagenbuch and Meier 2004). ABCC1, 3-5, and ABCG2 protein expression is also upregulated in alcoholic cirrhosis, and ABCC3-5 and ABCG2 protein expression is also upregulated in diabetic cirrhosis (More et al. 2013). The ABC transporter superfamily facilitates chemical efflux and includes multidrug resistance proteins (ABCB), multidrug resistance associated proteins (ABCC), bile salt export pump (ABCB11), and breast cancer resistance protein (ABCG2) (Choi and Yu 2014; ter Beek et al. 2014). In liver, ABCG2, ABCG2, and ABCBs are localized to the canalicular membrane and facilitate biliary excretion of chemicals. ABCC1 and 3-6 are localized sinusoidally or basolaterally and efflux chemicals from hepatocytes into blood. Cirrhosis increases NRF2 mRNA expression, whereas it decreases PXR and farnesoid X receptor (FXR) mRNA expression in comparison with normal livers (More et al. 2013). CYP3A4 and UGT1A3 mRNA expression is increased in livers with steatosis, while CYP2D6, UGT1A1, and 1A4 mRNA expression remains unchanged (More et al. 2013). In addition, tumor necrosis factor (TNF)-α and interleukin (IL)-1β mRNA levels are increased in alcoholic cirrhosis. These data demonstrate that alcoholic cirrhosis significantly alters the expression of multiple drug transporters but has a minor to moderate impact on the expression of CYPs (Zhou et al. 2003).
Therapeutic Perspective of Temozolomide Resistance in Glioblastoma Treatment
Published in Cancer Investigation, 2021
Qin Xia, Liqun Liu, Yang Li, Pei Zhang, Da Han, Lei Dong
In various types of CSCs and normal stem cells, the expression of drug transporters, such as ABC transporters is increased. GSCs expel drugs or decrease the drug uptake through increased expression of the ABC transporter, which is responsible for chemoresistance. ABC transporters transport molecules (such as TMZ) outside the cells, make a population of tumor cells evade treatment, and contribute to tumor recurrence. Warrier et al. found that CSCs resistant to doxorubicin (an anti-cancer drug) expressed elevated levels of ABC transporters, such as ABCG2 (ATP binding cassette subfamily G member 2), ABCC2 (ATP binding cassette transporter C2), and ABCC4 (ATP binding cassette transporter C4), which suggested that ABC transporters play a role in drug resistance (44). Indeed, it was found that compared with differentiated cancer cells, GSCs express ABC transporter channels at a higher rate, which makes the delivery of drugs more challenging due to the BBB and irregular vasculature (45).
Comprehensive palmitoyl-proteomic analysis identifies distinct protein signatures for large and small cancer-derived extracellular vesicles
Published in Journal of Extracellular Vesicles, 2020
Javier Mariscal, Tatyana Vagner, Minhyung Kim, Bo Zhou, Andrew Chin, Mandana Zandian, Michael R. Freeman, Sungyong You, Andries Zijlstra, Wei Yang, Dolores Di Vizio
Immunoblotting confirmed strong expression of STEAP1 in both populations of EVs from highly metastatic PC3 cells in comparison with the cells themselves (Figure 6(a)). This was not the case for purified EVs from DU145DIAPH3-KD cells (Suppl. Figure 2D-E), which is also highly metastatic, suggesting that STEAP1 expression in EVs is not indicative of disease aggressiveness. Conversely, STEAP2 was equally abundant in cells and both EVs from PC3 and DU145DIAPH3-KD cells (Figure 6(b)). Finally, ABCC4 was highly enriched in EVs from PC3 and DU145DIAPH3-KD cells in contrast to the low expression detected in the parental cells (Figure 6(c)). We also analysed these proteins at the single EV level using flow cytometry, and found that STEAP1 was highly expressed in both PC3 and DU145DIAPH3-KD L-EVs but virtually undetectable in PC3 cells (Figure 6(d)). STEAP2 was highly abundant in both L-EVs and cells (Figure 6(e)). ABCC4 was relatively enriched in L-EVs versus cells (Figure 6(f)). Collectively, these results indicate that prostate cancer-specific proteins enriched in EVs are not necessarily abundant in cancer tissue and support the use of EV cargo as a source of clinically relevant circulating biomarkers.
Important pharmacogenomic aspects in the management of HIV/AIDS
Published in South African Family Practice, 2019
A Marais, E Osuch, V Steenkamp, L Ledwaba
The intracellular pharmacology of the NRTIs is a major determinant of their activity and toxicity, as these drugs are not metabolised by the hepatic CYP450 enzyme system. Tenofovir acts as an adenosine monophosphate nucleoside analogue resulting in the inhibition of HIV replication by causing DNA chain termination. It is metabolised intracellularly through phosphorylation by cellular adenylate kinase and excreted by the kidneys through glomerular filtration and active tubular secretion.23 Several pharmacogenetic studies assessing the variants in the ABCC4 gene, commonly implicated in multidrug resistance, were unable to show any association between tenofovir resistance and protein expression in Caucasian populations.24 Emtricitabine similarly results in DNA chain termination and thus inhibition of HIV replication. It acts as nucleoside analogue of cytosine and likewise phosphorylated by intracellular enzymes independent of the hepatic CYP450 enzyme system.25 Applicable pharmacogenetic evidence is absent in studies concerning emtricitabine.