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Modulators of multidrug resistance associated proteins in the management of anticancer and antimicrobial drug resistance and the treatment of inflammatory diseases.
- Source :
-
Current topics in medicinal chemistry [Curr Top Med Chem] 2010; Vol. 10 (17), pp. 1732-56. - Publication Year :
- 2010
-
Abstract
- Human multidrug resistance protein (MRP/ABCC) family contains 9 members (MRP1-9) which transport a structurally diverse array of anticancer and antimicrobial drugs and several important endogenous substances including prostaglandins (PGs) and leukotrienes (LTs) with different substrate specificity. MRP1-5 can collectively confer resistance to natural product anticancer drugs and their conjugated metabolites, platinum compounds, folate antimetabolites, nucleoside and nucleotide analogs, and alkylating agents. MRP1-3 are often associated with tumor resistance which is often caused by an increased efflux and decreased intracellular accumulation of natural product anticancer drugs and other anticancer agents. Both PGE(1) and PGE(2) are known high-affinity substrates of MRP4, but not MRP1, MRP2, MRP3 and MRP5. LTC(4) is a substrate of MRP1, MRP2, MRP3, and MRP6-8. MRP2 is also able to transport LTD(4) and LTE(4). Experimental studies in Abcc1-difficient mice have demonstrated a role of MRP1 in inflammation process in vivo. Abcc3-difficient mice have normal bile salt transport, however they have decreased blood bilirubin glucuronide levels. Abcc6-difficient mice show remarkable mineraliztion of the connective tissues, including skin, arterial blood vessels, and retina. Most MRP/ABCC transporters are subject to inhibition by a variety of compounds. Drug targeting of these transporters to overcome MRP/ABCC-mediated multidrug resistance may play a role in cancer and infection (e.g. HIV infection) chemotherapy. Some modulators of MRPs have shown reversing effects on MDR phenotype in preliminary clinical studies and some modulators of MRPs may modify the inflammatory process and consequently ameliorate the inflammatory symptoms. A better understanding of the interactions of these modulators with MRPs has important implications in development of novel drugs for treatment of cancer, infection and inflammation.
- Subjects :
- Animals
Antineoplastic Agents chemistry
Antineoplastic Agents immunology
Drug Resistance, Multiple drug effects
Drug Resistance, Neoplasm drug effects
Humans
Inflammation
Inflammation Mediators chemistry
Inflammation Mediators immunology
Multidrug Resistance-Associated Proteins immunology
Neoplasms immunology
Antineoplastic Agents pharmacology
Inflammation Mediators pharmacology
Multidrug Resistance-Associated Proteins antagonists & inhibitors
Neoplasms drug therapy
Subjects
Details
- Language :
- English
- ISSN :
- 1873-4294
- Volume :
- 10
- Issue :
- 17
- Database :
- MEDLINE
- Journal :
- Current topics in medicinal chemistry
- Publication Type :
- Academic Journal
- Accession number :
- 20645920
- Full Text :
- https://doi.org/10.2174/156802610792928040