TY - JOUR
T1 - Modulators of multidrug resistance proteins in the management of anticancer and antimicrobial drug resistance and the treatment of inflammatory diseases
AU - Yang, An Kui
AU - Zhou, Zhi Wei
AU - Wei, Min Qian
AU - Liu, Jun Ping
AU - Zhou, Shu Feng
PY - 2010
Y1 - 2010
N2 - 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 of-ten caused by an increased efflux and decreased intracellular accumulation of natural product anticancer drugs and other anticancer agents. Both PGE1 and PGE2 are known high-affinity substrates of MRP4, but not MRP1, MRP2, MRP3 and MRP5. LTC4 is a substrate of MRP1, MRP2, MRP3, and MRP6-8. MRP2 is also able to transport LTD4 and LTE4. Experimental studies in Abcc1-defficient mice have demonstrated a role of MRP1 in inflammation process in vivo. Abcc3-deficcient mice have normal bile salt transport, however, they have decreased blood bilirubin glucuronide levels. Abcc6-deficient mice show remarkable mineralization 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.
AB - 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 of-ten caused by an increased efflux and decreased intracellular accumulation of natural product anticancer drugs and other anticancer agents. Both PGE1 and PGE2 are known high-affinity substrates of MRP4, but not MRP1, MRP2, MRP3 and MRP5. LTC4 is a substrate of MRP1, MRP2, MRP3, and MRP6-8. MRP2 is also able to transport LTD4 and LTE4. Experimental studies in Abcc1-defficient mice have demonstrated a role of MRP1 in inflammation process in vivo. Abcc3-deficcient mice have normal bile salt transport, however, they have decreased blood bilirubin glucuronide levels. Abcc6-deficient mice show remarkable mineralization 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.
KW - Cancer
KW - Chemotherapy
KW - Drug resistance
KW - Inflammatory disease
KW - Inhibitor
KW - MRP
KW - Substrate
UR - http://www.scopus.com/inward/record.url?scp=77958012886&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=77958012886&partnerID=8YFLogxK
U2 - 10.2174/156802610792928040
DO - 10.2174/156802610792928040
M3 - Article
C2 - 20645920
AN - SCOPUS:77958012886
SN - 1568-0266
VL - 10
SP - 1732
EP - 1756
JO - Current topics in medicinal chemistry
JF - Current topics in medicinal chemistry
IS - 17
ER -