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Opioids Analgesics and Antagonists
Published in Sahab Uddin, Rashid Mamunur, Advances in Neuropharmacology, 2020
R. Rachana, Tanya Gupta, Saumya Yadav, Manisha Singh
CYPD26, cytochrome P450 2D6; CYP3A, cytochrome P450 3A4; UGT2B7, UDP-glucuronosyltransferase-2B7; C6G, codeine-6-glucuronide; M3G, morphine-3-glucuronide; M6G, morphine-6-glucuronide; ABCC2, ATP-binding cassette sub-family C member 2; ABCC3, ATP-binding cassette sub-family C member 3.
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).
A novel tumor-homing TRAIL variant eradicates tumor xenografts of refractory colorectal cancer cells in combination with tumor cell-targeted photodynamic therapy
Published in Drug Delivery, 2022
Zhao Li, Tianshan She, Hao Yang, Tao Su, Qiuxiao Shi, Ze Tao, Yanru Feng, Fen Yang, Jingqiu Cheng, Xiaofeng Lu
The chemotherapeutic MDR of cancer cells is predominantly attributed to overexpressed chemical efflux pumps, such as ABC transporters. To investigate the expression of ABC transporters in tumor tissues derived from CRC patients, public RNA-seq data obtained from TCGA and GTEx were analyzed by GEPIA. As shown in Figure 1(A) and Supplementary Figure S1, bioinformatics analysis demonstrated that the tumor tissue levels of ABC transporters, including ABCB1, ABCB7, ABCC1, ABCC2, ABCC3, ABCC4, ABCC6, ABCC10, ABCC11, and ABCG1, were significantly higher than those in normal tissues, suggesting the MDR of CRC cells. In fact, cytotoxicity assays revealed that CRC cells, such as COLO205, HCT116, LS174T, and HT29, showed resistance (IC50 > 1000 nM) to all tested chemical drugs, including cisplatin, vincristine, doxorubicin, and bortezomib (Figure 1(B)). Interestingly, bioinformatics analysis also demonstrated that death receptors, including DR4 and DR5, were overexpressed in CRC tumor tissues (Figure 1(A)), suggesting the potential of TRAIL as an anticancer agent for CRC. In fact, TRAIL showed robustly (ICs50 < 10 nM) cytotoxicity in CRC cells, including COLO205, HCT116, and LS174T cells overexpressing DR5 and/or DR4 (Figure 1(C, D)), indicating that TRAIL might overcome the chemotherapeutic MDR of CRC cells. Nevertheless, due to the low expression of death receptors, some CRC cells, such as HT29, showed moderate resistance (IC50s > 50 nM) to TRAIL (Figure 1(C, D)), suggesting the need to improve the cytotoxicity of TRAIL in these cells.
Population pharmacokinetics of methotrexate in paediatric patients with acute lymphoblastic leukaemia and malignant lymphoma
Published in Xenobiotica, 2022
Min Zhan, Yiqi Sun, Fang Zhou, Honghong Wang, Zebin Chen, Lianzhen Yan, Xingang Li
ABCC3 is a member of the multidrug resistance protein (MRP) family. MTX has been suggested to be one of the ABCC3 substrates. Caronia et al. (2011) indicated that the expression of ABCC3 mRNA is related to drug resistance and the T allele of the synonymous SNP rs4148416 in the ABCC3 gene was associated with a higher risk of death as compared to allele C in people with osteosarcoma. Our results show that the gene polymorphism most associated with MTX clearance was rs4148416, and the CC genotype carriers of rs4148416 have an increased elimination of MTX compared to TT genotype carriers. SNP rs4148416 locates in exon 22 of ABCC3. The mutation in rs4148416 did not lead to an amino acid substitution. It was predicted to be a site of Exonic Splicing Enhancer or Exonic Splicing Silencer (https://snpinfo.niehs.nih.gov/cgi-bin/snpinfo/splice.cgi?2_rs4148416). We speculated the synonymous mutation (rs4148416, C > T) maybe affect the splice of the ABCC3, resulting in alteration of ABCC3 mRNA and protein level.
Survival gain in glioblastoma patients treated with dendritic cell immunotherapy is associated with increased NK but not CD8+ T cell activation in the presence of adjuvant temozolomide
Published in OncoImmunology, 2018
Serena Pellegatta, Marica Eoli, Valeria Cuccarini, Elena Anghileri, Bianca Pollo, Sara Pessina, Simona Frigerio, Maura Servida, Lucia Cuppini, Carlo Antozzi, Stefania Cuzzubbo, Cristina Corbetta, Rosina Paterra, Francesco Acerbi, Paolo Ferroli, Francesco DiMeco, Laura Fariselli, Eugenio A. Parati, Maria Grazia Bruzzone, Gaetano Finocchiaro
The poor contribution of CD8+ T cells to anti-tumor responses was partly compensated by strong and long-lasting NK cell responses. In order to understand this persistency, we investigated the potential involvement of the multidrug resistance protein ABCC3, based on our preclinical evidence that the efflux activity of ABCC3 confers chemoresistance to NK cells and protection from apoptotic cell death.18 Abcc3 expression, investigated by real-time PCR, was significantly higher in responders (n = 8) than non-responders (n = 9; P = 0.0005) at the time of first vaccination after standard radio-chemotherapy (P = 0.02) and remained higher after concomitant vaccine and TMZ administration (P < 0.01) (Fig. 5C). Using flow cytometry, we found that ABCC3 was expressed by NK cells but not by CD8+ T lymphocytes also in PBLs from 3 healthy volunteers (68.6 ± 16.8 vs. 1.2 ± 0.8, respectively; P = 0.0002, not shown). We also verified that at the time of leukapheresis (i.e. before radiochemotherapy), NK cells from responders displayed higher basal expression of ABCC3 than non-responders (28.7 ± 29.6% vs. 15.8 ± 17.6%, respectively; P = 0.02) (Fig. 5D). Responders showed a further increase of ABCC3 after DC vaccinations and concomitant TMZ. In CD8+ T lymphocytes basal expression of ABCC3 was negligible (Fig. 5E) and in CD4+ T lymphocytes quite low (Fig. 5F).