Lung cancer inhalation therapeutics
Anthony J. Hickey, Heidi M. Mansour in Inhalation Aerosols, 2019
Resistance to anticancer agents could develop by several mechanisms, including decreased drug influx, increased drug efflux, activation of DNA repair, detoxification, and inactivation of apoptosis. A large family of transmembrane proteins, ATP-binding cassette (ABC) transporters, are ATP-dependent efflux systems that expel anticancer drugs from the cytoplasm out of the cells and reduce their intracellular concentration. These transmembrane efflux proteins include P-glycoprotein (P-gp), multidrug resistance-associated proteins (MRPs), and breast cancer resistant protein (BRCP) and appear to account for most of the reported multidrug resistance in humans. The overexpression of specific ABC transporters in cancer cell lines and tumors produces multi-drug resistance, which is the major factor contributing to the failure of chemotherapy (143).
Garcinia indica (Kokum) and Ilex aquifolium (European Holly)
Azamal Husen in Herbs, Shrubs, and Trees of Potential Medicinal Benefits, 2022
Connectivity map approach indicates that UA exhibit inhibitory effect against breast cancer cells by modulating some of the key pathways including PLK1, IKK/NF-κB, and RAF/ERK pathways (Guo et al., 2020). In addition, downregulation of Nrf-2, PI3K/AKT, JNK pathway were also reported (Zhang et al., 2020; Luo et al., 2017; Yeh et al., 2010). UA sensitized the triple negative breast cancer cells to doxorubicin and enhances apoptosis by targeting ZEB1-AS1/miR-186-5p/ABCC1 axis (Lu et al., 2021). ATP-binding cassette transporter C (ABCC1) are transporters that mediates the efflux of drugs from cancer cells, preventing their accumulation and causing chemoresistance. UA inhibits the growth of breast cancer stem-like cells by attenuating sFRP4 mediated Wnt/β-catenin pathway and suppressing miRNA-499a-5p involved in invasion and metastasis (Mandal et al., 2021).
Genetics and Biosynthesis of Lipopolysaccharide O-Antigens
Helmut Brade, Steven M. Opal, Stefanie N. Vogel, David C. Morrison in Endotoxin in Health and Disease, 2020
Studies with Yersinia enterocolitica serotype 0:3 first showed intracellular O-PS accumulation in this pathway (82). Electron microscopy subsequently confirmed the cytoplasmic location of O-PS in K. pneumoniae Ol mutants (83). In both cases, surface assembly requires a plasma membrane ABC transporter encoded by the O-PS biosynthesis cluster (Fig. 2D) (82,83). There is therefore no requirement for a Wzx homolog in this pathway. The genes for the ABC transporters were identified based on predicted protein sequence homologies with the ABC-2 subfamily of transporters (84). ABC-2 transporters consist of an integral membrane protein with an average of six membrane-spanning domains and a hydrophilic protein containing an ATP-binding motif or Walker box. The genes for these two components have now been identified in a number of O-PS biosynthesis clusters (Table 2). As with other ABC transporters involved in transmembrane export, the membrane-spanning (Wzm) homologs for O-PS biosynthesis generally exhibit little primary sequence identity but have nearly identical hydropathy plots (83,85). In contrast, primary sequences of the ATP-binding (Wzt) homologs are much more highly conserved, with the highest degree of sequence homology in the nucleotide-binding region (83,85).
Overcoming multidrug resistance through targeting ABC transporters: lessons for drug discovery
Published in Expert Opinion on Drug Discovery, 2022
Mohammad Feyzizadeh, Ashkan Barfar, Zeinab Nouri, Muhammad Sarfraz, Parvin Zakeri-Milani, Hadi Valizadeh
Biedler et al. pointed out that a cell surface protein could mediate the potential existence of MDR phenomenon[7]. MDR is one of the problems in the drug treatment process and may occur in many fungal diseases, bacteria, and cancer. In some bacteria, enzyme inactivation mechanisms like phosphorylation arrest aminoglycosides’ activity [8]. Some fungi develop drug resistance to fluconazole by changing the direction of ergosterol [9]. Common mechanisms of MDR between different organisms are efflux pumps or ABC transporters, which are naturally present in cells and play a significant role in maintaining their homeostasis [10]. ABC transporters are the significant components of the membrane protein superfamily that translocate different molecules like drugs across extra/intracellular membranes, which need to consume ATP to mediate the movement of their substrates across cell membranes. They are separated into subfamilies that in humans are ABCA to ABCG. On the other hand, plants possess ABCI in addition to ABCA to ABCG but do not have ABCH [11].
Efflux transporter breast cancer resistance protein dominantly expresses on the membrane of red blood cells, hinders partitioning of its substrates into the cells, and alters drug–drug interaction profiles
Published in Xenobiotica, 2018
Pu Shi, Mingxiang Liao, Bei-Ching Chuang, Robert Griffin, Judy Shi, Marc Hyer, John K. Fallon, Philip C. Smith, Chao Li, Cindy Q. Xia
Small molecule compounds cross cell membranes and enter cells via two distinct mechanisms, passive diffusion and active transport (Hogben, 1963). ATP-binding cassette (ABC) transporters are one of the largest families of transporters. They energize the translocation of various substrates across cellular membranes using adenosine triphosphate (ATP) (Davidson et al., 2008; Jones & George, 2004). BCRP (ABCG2) and P-gp (MDR1 or ABCB1) are two major ABC transporters found on cellular membranes (Doyle et al., 1998; Ling, 1997). They are extensively distributed and expressed in the intestinal epithelium, hepatocytes and capillary endothelial cells of the blood–brain barrier. They lower the intracellular concentration of substrates by pumping them out of the cells against the gradient (International Transporter Consortium et al., 2010; Vlaming et al., 2009). Numerous studies have confirmed that drug transporters are critical for in vivo drug distribution and disposition and therapeutic efficacy and can contribute to adverse effects (Cascorbi, 2006; Jonker et al., 2003; Maeda & Sugiyama, 2008; Schinkel et al., 1995; Sissung et al., 2008). Drug transporters have been implicated in clinical PK DDI studies to work synergistically with drug-metabolizing enzymes (DMEs) in drug absorption and elimination (International Transporter Consortium et al., 2010; Pang et al., 2009).
PTD modified paclitaxel anti-resistant liposomes for treatment of drug-resistant non-small cell lung cancer
Published in Journal of Liposome Research, 2018
Rui-jun Ju, Lan Cheng, Yao Xiao, Xin Wang, Cui-qing Li, Xiao-ming Peng, Xue-tao Li
ABC transporters are members of a transport system superfamily, which mainly involved in multidrug resistance (Egido et al., 2015). ABC transporters utilize the energy of ATP binding and hydrolysis to transport various substrates across cellular membranes (Wang et al., 2015). When ABC transporters are overexpressed in cancer cells, they can export anticancer drugs and render resistance to chemotherapies (Lima et al., 2015; Qiu et al., 2015). Results showed that the expressions of ABC transporters in resistant LLT cells were evidently higher than those in LLT cells, indicating a resistance to anticancer drugs within the resistant LLT cells. The expressions of ABCB1, ABCC1 and ABCG2 in resistant LLT cells were significantly down-regulated after treatment with paclitaxel anti-resistant liposomes or PTD modified paclitaxel anti-resistant liposomes (Figure 9), suggesting that the incorporation of tamoxifen in the liposomes could circumvent the drug resistance.
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