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Nanocarriers as an Emerging Platform for Cancer Therapy
Published in Lajos P. Balogh, Nano-Enabled Medical Applications, 2020
Dan Peer, Jeffrey M. Karp, Seungpyo Hong, Omid C. Farokhzad, Rimona Margalit, Robert Langer
Among the MDR transporters, the most widely investigated proteins are: P-glycoprotein (also referred to as MDR1 or ABCB1); the multidrug resistance associated proteins (MRPs), of which the most studied is the MRP1 (or ABCC1); and the breast cancer resistance protein (ABCG2). These proteins have different structures, but they share a similar function of expelling chemotherapy drugs from the cells [12]. Several studies have demonstrated the possibility of using nanocarriers to bypass the MDR transporters. SP1049C is a non-ionic (pluronic or also known as poloxamer) block copolymer composed of a hydrophobic core and hydrophilic tail that contains doxorubicin. SP1049C has been shown to circumvent p-glycoprotein-mediated drug resistance in a mouse model of leukaemia and is now under clinical evaluation [91, 92]. Folate receptor-mediated cell uptake of doxorubicin–loaded liposomes into an MDR cell line was shown to be unaffected by P-glycoprotein (Pgp)-mediated drug efflux, in contrast to the uptake of free doxorubicin [93]. In an attempt to reverse MDR, vincristine-loaded lipid nanoparticles conjugated to an anti-Pgp mAb (MRK-16), showed greater cytotoxicity in resistant human myelogenous leukaemia cell lines than control non-targeted particles—a response attributed to the inhibition of the Pgp-mediated efflux of vincristine by MRK-16 [94]. Additional reports have addressed the challenge of MDR using polymer therapeutics95, polymeric nanoparticles [96], lipid nanocapsules [97] and micelles [98] within cell lines or in mouse tumour models. Combination treatments with targeted nanocarriers for selective delivery of drugs and MDR pump inhibitors will likely address some of the problems posed by resistant tumours.
Plant-Based Compounds as Alternative Adjuvant Therapy for Multidrug-Resistant Cancer
Published in Parimelazhagan Thangaraj, Phytomedicine, 2020
E. C. Aniogo, Blassan P. George, Heidi Abrahamse
One of the most widely known resistance mechanisms is through altered membrane transport by adenosine triphosphate (ATP)-binding cassette (ABC) transporters. The ABC transporters belong to the ubiquitous superfamily of transmembrane proteins that modulate drug and other biomolecules absorption, distribution, and excretion across cell membrane. Today, there are 48 identified human ABC genes grouped into seven subclasses (A–G) based on their sequence of homology and genomic organization (Chorawala et al. 2012; Eid et al. 2015). In clinical transport-associated multidrug resistance, the MDR1 gene, which encodes for P-glycoprotein (P-gp; MDR1, ABCB1), is the widely studied. The P-gp has two highly hydrophobic integral membrane and nucleotide-binding domains that make up its structure. This structure enables them to efficiently efflux cytotoxic drugs through a “pump” and “flippase” model of transport from the inner leaflet to the outer leaflet of the lipid bilayer into the extracellular space (Sharom 2014). Other ABC transporters: the multidrug resistance-associated protein 1 (MRP-1, ABCC1) and the breast cancer-resistant protein (BCRP, ABCG2) have been implicated as major efflux transporters responsible for cancer resistance in chemotherapy (Mao and Unadkat 2015). The MRP1 is similar in structure with the P-gp/MDR1 and contains an added amino terminal in the domains attached to the core that can recognize both neutral and anionic hydrophobic natural products and transports glutathione (Eid et al. 2015). The ABCG2 gene located at 4q22 encodes human BCRP. Structurally, the BCRP contains an ATP-binding domain and six transmembrane segments in a homodimer of two-half transporters. The BCRP is highly expressed and widely distributed in the gastrointestinal tract, excretory tissue, and blood-tissue barriers (Fletcher et al. 2016).
Buthionine sulfoximine and chemoresistance in cancer treatments: a systematic review with meta-analysis of preclinical studies
Published in Journal of Toxicology and Environmental Health, Part B, 2023
Camila dos Reis Oliveira, Joedna Cavalcante Pereira, Andressa Barros Ibiapina, Italo Rossi Roseno Martins, João Marcelo de Castro e Sousa, Paulo Michel Pinheiro Ferreira, Felipe Cavalcanti Carneiro da Silva
In this context, GSH in tumor cells may act to diminish the effectiveness of chemotherapy agents as follows: GSH might react with electrophilic intermediates present in chemotherapy drugs, thus preventing these therapeutic intermediates from reaching the target site, and being re-directed to the extracellular environment through interaction with MRP1 transporters (Gana et al. 2019; Huber, Almeida, and Fátima 2008). Whitt et al. (2016) also noted that BSO selectively increased sensitivity to sulindac sulfide-induced cytotoxicity in cells expressing ABCC1. Therefore, ATP-binding cassette (ABC) transporters ABCC1 (MRP1), ABCB1 (P-gp), and ABCG2 (BCRP) also contribute to chemotherapy failure (Whitt et al. 2016).