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    • br ABCA and cancer drug response Overall the expression

    2023-04-12


    ABCA2 and cancer drug response Overall, the expression of ABC transporters has been linked with multidrug resistance phenotypes through the efflux of drugs via ATP-dependent transport. For example, 13 distinct transporters (ABCA2, ABCB1, ABCB4, ABCB11, ABCC1–6 ABCC10, ABCC11 and ABCG2) have been associated with drug transport/resistance [23]. Historically, members of the MDR and MRP subfamilies (e.g. ABCB1/MDR1 and ABCC1/MRP1) have garnered the most attention [1], since their primary functions appear to be with efflux of foreign compounds such as cancer drugs. ABCA2 expression has been measured in cancer cell lines, (especially those with acquired drug resistance), normal and cancer stem Bilirubin and in human biopsies from cancer patients undergoing therapy. In most instances correlations were drawn between the extent of expression and drug response in the samples. The first report [5] was in an ovarian carcinoma cell line with acquired resistance to estramustine (EM). These selected cells amplified a region in chromosome 9q34, resulting in 5-fold increase in ABCA2 expression and an increased rate of efflux of dansyl-labeled EM. The resistance rendered by ABCA2 expression was reversed upon antisense treatment [5]. Resistance to EM and estradiol was also shown in transfected HEK293 cells [12], but not in dominant negative ABCA2 transfected cells [20] and further cross resistance to a free radical initiator, 2,2′-azobis-(2-amidinopropane) (AAPH) [24], a compound structurally unrelated to steroids [25] was also detailed. ABCA2 may mediate the transport and sequestration of damaged lipids into the lysosome, preventing any propagation of chain reactions, where initiation, propagation and termination of lipid peroxides are prevented. ABCA2 was also linked with resistance to mitoxantrone and EM in a small cell lung cancer cell line [26] and treatment with both agents caused accumulation of mitoxantrone, indicating that EM may block its transport, although there was no direct proof that ABCA2 was the mediator of the transport. ABCA2 was also over-expressed in a daunorubicin-resistant promyelocytic leukemia cell line [27]. Overall, ABCA2 has been implicated in resistance to a diverse range of compounds, both sterol and non-sterol. The localization of ABCA2 to intracellular membrane organelles suggests that enhanced ABCA2 levels may protect cells through sequestration of toxic products into lysosomes, where specific examples have been shown [28]. Perhaps post-translational modifications may also influence substrate specificity and these could be both species and organ specific. Recently, Celecoxib has been shown to sensitize tumor cells resistant to the tyrosine kinase inhibitor imatinib. The authors concluded that this reversal was mediated at least in part by inhibition of ABCA2 [29]. Many cancers also have deregulated cholesterol metabolism and it is a critical early precursor for a number of pathways that influence the development and progression of cancer [30]. Hormones can influence cholesterol metabolism in cancer patients [31] and interfere with cholesterol metabolic pathways (e.g. HMGCoA R inhibition via statins) has been suggested to be a possible target in the therapeutic management of cancer patients [32]. Lysosomes in cancer cells have been suggested as viable drug targets [33]. Reducing the availability of this essential component of membranes and lipid raft domains may influence survival in rapidly dividing cancer cells. The plausible role of ABCA2 in regulating availability of cholesterol may validate it as a target for drug development. There is now a better understanding of the importance of cancer stem cells as the arbiters of drug resistance. These cells have many of the properties of normal stem cells that permit them to survive chemotherapy, including high expression of various ABC transporters [34]. Such stem cells can provide a reserve of drug resistant progenitor cells that might repopulate the tumor following chemotherapy. ABC transporter over-expression is not uncommon among normal and malignant hematopoietic stem cells [35]. In AML progenitor cells, ABCA2 expression was significantly enriched in CD34+CD38− cells compared to more differentiated CD34+CD38+ cells [36]. These CD34+CD38− cells have greater malignant and self-renewing properties and such observations concur with the fact that ABCA2 expression has been implicated in leukemic cell multi-drug resistance in both AML [37] and T-ALL [38]. ABCA2 is also prevalent in some pluripotent side populations of lung cancer cells. These cells had high expression of ABCA2, ABCG2, ABCB1 and ABCC1 and showed resistance to a range of anticancer drugs. These cells also displayed stem cell properties indicative of a quiescent state, but higher replicative potential [39].