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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).
Activation of CXCL12-CXCR4 signalling induces conversion of immortalised embryonic kidney cells into cancer stem-like cells
Published in Artificial Cells, Nanomedicine, and Biotechnology, 2020
Seung-ick Oh, Hyesun Jeong, Hang-soo Park, Kyung-Ah Choi, Insik Hwang, Jiyun Lee, Jeonghee Cho, Sunghoi Hong
To examine the level of ABC-binding cassette transporters, known to be highly expressed in CSCs [21], we performed real-time RT-PCR experiments with the total RNA isolated from suspension-cultured iCSC lines. The expression levels of Abcc1, Abcc2, Abcc3, Abcc5, and Abcb1 genes were significantly increased, but not Abcc4, Abcc6, Abcg2, and Abca2 (Figure 5(e)). Taken together, these results demonstrate that the cells constituting the spheres were highly chemoresistant, indicating that our iCSC lines possess the typical properties of CSCs. Interestingly, we found that the cells in the primary spheres were strongly positive against NSC markers (CD15, CD133, NESTIN, SOX2 or NCAM) [22] and stem cell marker (OCT4) antibodies (Figure 6(a)) when the iCSC lines were grown as spheres, suggesting that a population of cells consisting of iCSC may be CSCs with neural lineage properties.
Efflux proteins at the blood–brain barrier: review and bioinformatics analysis
Published in Xenobiotica, 2018
Massoud Saidijam, Fatemeh Karimi Dermani, Sareh Sohrabi, Simon G. Patching
MRP4 (ABCC4) and MRP5 (ABCC5), which share 36.3% sequence identity, were both discovered in 1997 by screening databases of human expressed sequence tags (Kool et al., 1997). Substrates of MRP4 include nucleotide analogues (e.g. cAMP, cGMP, PMEA), glucuronide conjugates (e.g. E217βG), sulphate conjugates (e.g. DHEAS), prostaglandins (PGE1, PGE2), methotrexate and bile acids. Substrates of MRP5 include nucleotide and nucleoside analogues (e.g. cAMP, cGMP, PMEA, 5′-FUMP), glutathione and glutathione conjugates (e.g. DNP-SG) (Deeley & Cole, 2006). Indeed, a major distinction between the substrate specificities of MRP4 and MRP5 compared with MRP1 and MRP2 is their ability to transport nucleoside and nucleotide analogues, as well as cyclic nucleotides. This provides them with an ability to confer resistance to certain antiviral and anticancer nucleotide analogue drugs. MRP5 has recently been demonstrated as an efflux transporter of glutamate conjugates and analogues, which affects the disposition of endogenous metabolites, drugs and xenobiotics (Jansen et al., 2015). MRP4 has been detected on the luminal surface of rat cerebral microvessels by both immunofluorescence staining and Western blotting of in vivo biotinylated protein, whilst MRP5 was not detected by either method (Roberts et al., 2008). A different study used immunofluorescence staining to detect MRP5 on the luminal side of mouse brain endothelial cells (Soontornmalai et al., 2006). Confocal laser scanning microscopy detected both MRP4 and MRP5 at the luminal side of human brain capillary endothelial cells. MRP4 and MRP5 were also detected in astrocytes of the subcortical white matter (Nies et al., 2004). The same method used with bovine brain microvessel endothelial cells detected an almost equal distribution of MRP4 at luminal and abluminal membranes and a primarily luminal localisation of MRP5 (Zhang et al., 2004). The expression and activity of both MRP4 and MRP5 have also been detected in microglia. Here they could restrict permeation of several different classes of antiretroviral drugs in a brain cellular target of HIV-1 infection, which has implications for HIV-associated dementia (Dallas et al., 2004).
Priming of pancreatic cancer cells with bispecific antibody armed activated T cells sensitizes tumors for enhanced chemoresponsiveness
Published in OncoImmunology, 2021
Archana Thakur, Johnson Ung, Elyse N. Tomaszewski, Amy Schienschang, Timothy M. LaBrie, Dana L. Schalk, Lawrence G. Lum
Drug resistance (both intrinsic and acquired) is thought to be a major reason for the limited benefit of most pancreatic cancer therapies.27 MDR is mediated by various mechanisms involving numerous proteins belonging to a larger family of the ATP-binding cassette (ABC) transporter superfamily that play key roles in drug efflux and MDR.14 ABC transporters, such as MRP-1 (ABCC1), MRP-5 (ABCC5), ABCG2, and MDR-1 are shown to confer resistance to pancreatic cancer against common chemotherapeutic drugs.17,25 Overexpression of drug efflux pumps leads to decreased intracellular drug accumulation which contributes to drug resistance.28 Our data shows that priming cancer cells with BATs results in enhanced cytotoxicity by chemotherapy drug and decreased expression of MRP-1, ABCG2, MDR-1, and ABCC5 in both parental and CIS-resistant PANC-1 cell lines by flow cytometry. In MiaPaCa-2 cells, enhanced cytotoxicity was observed by chemotherapy drug after priming with BATs but expression of drug efflux pumps increased after priming. These data suggest the possibility that increased expression of drug transporters in BATs primed tumor cells may enhance in vivo sensitivity for immunotherapy based on the fact that these pumps can transport intracellular peptides for major histocompatibility complex class I antigen presentation.29 Since we did not see decrease in efflux transporters in MiaPaCa-2 cells, we hypothesized that enhanced cytotoxic effect of chemotherapy in BATs sensitized MiaPaCa-2 is likely due to IFN-γ released during tumor cells' engagement by BATs. To validate our hypothesis, we tested culture supernatant from MiaPaCa-2 and BATs co-culture, to prime freshly plated MiaPaCa-2 cells followed by washing and adding 25% or 50% lower dose of IC50 CIS concentrations, which showed enhanced cytotoxicity compared to unprimed MiaCaPa-2 cells (Fig. S2). Previous studies have shown that nonspecifically activated CD4+ T cells chemosensitize tumor cells and IFN-γ was shown to play a major role. Since Th1 cytokines are released during BATs mediated killing of tumor cells, it is likely that Th1 cytokines modulate the tumor microenvironment to enhance endogenous cellular and humoral anti-tumor immune responses and may sensitize the tumor for enhanced, subsequent chemotherapeutic responsiveness.30