MRP1 and MRP2, founding members of the MRP family, are involved in cellular resistance to anticancer agents and drug disposition in the body. Studies in our laboratory and others now indicate that the MRP family extends to 9 members. In the previous funding period we focused on the analysis of the in vivo functions of MRP3 and MRP4, and on the elucidation of the functional properties of MRP6, MRP7 and MRP8. To accomplish this we developed and analyzed mrp3 and mrp4 knock-out mice and cell lines in which MRP6, MRP7 and MRP8 were ectopically expressed. Using our mrp3 knock-out mice, we showed that the Mrp3 functions in liver as a basolateral efflux pump for sulfate metabolites of xenobiotics, and that it similarly protects cholestatic liver from endogenous compounds such as bile acids. Our studies on Mrp4 knockout mice showed that Mrp4 is an in vivo resistance factor for the antiviral nucleotide analog PMEA, restricts penetration of this agent into brain, and like Mrp3, functions in the basolateral extrusion of sulfates from hepatocytes. MRP6, MRP7 and MRP8 were determined to be lipophilic anion transporters that are able to confer cellular resistance to anticancer natural product (MRP6, MRP7) and nucleoside-based agents (MRP8). In this application we propose to define the pharmacological functions of MRP4 as an in vivo resistance factor for anticancer agents, and as a component of the blood-brain and blood-cerebrospinal fluid barriers for anticancer agents. In addition, we will complete our investigation of the newly discovered MRP family members by determining the drug resistance abilities and substrate selectivity of MRP9 - the only MRP whose functional properties have not been determined to any extent. These studies will provide insights into factors that reduce the effectiveness of chemotherapeutic agents, as well as into medically relevant physiological processes in which these unusual pumps are involved.

Public Health Relevance

The experiments in this proposal will promote public health by providing information on why many types of cancers are not successfully treated with anticancer agents. This information should assist in the development of agents and strategies that are more successful.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA073728-12
Application #
8338778
Study Section
Basic Mechanisms of Cancer Therapeutics Study Section (BMCT)
Program Officer
Forry, Suzanne L
Project Start
1999-09-01
Project End
2014-06-30
Budget Start
2012-07-01
Budget End
2013-06-30
Support Year
12
Fiscal Year
2012
Total Cost
$463,871
Indirect Cost
$267,346
Name
Icahn School of Medicine at Mount Sinai
Department
Pharmacology
Type
Schools of Medicine
DUNS #
078861598
City
New York
State
NY
Country
United States
Zip Code
10029
Sane, Ramola; Wu, Shu-Pei; Zhang, Rong et al. (2014) The effect of ABCG2 and ABCC4 on the pharmacokinetics of methotrexate in the brain. Drug Metab Dispos 42:537-40
Gallo, J M (2013) Physiologically based pharmacokinetic models of tyrosine kinase inhibitors: a systems pharmacological approach to drug disposition. Clin Pharmacol Ther 93:236-8
Wang, Fan; Zhou, Feng; Kruh, Gary D et al. (2010) Influence of blood-brain barrier efflux pumps on the distribution of vincristine in brain and brain tumors. Neuro Oncol 12:1043-9
Zhou, Ying; Hopper-Borge, Elizabeth; Shen, Tong et al. (2009) Cepharanthine is a potent reversal agent for MRP7(ABCC10)-mediated multidrug resistance. Biochem Pharmacol 77:993-1001
Hopper-Borge, Elizabeth; Xu, Xiu; Shen, Tong et al. (2009) Human multidrug resistance protein 7 (ABCC10) is a resistance factor for nucleoside analogues and epothilone B. Cancer Res 69:178-84
Guo, Yanping; Kock, Kathleen; Ritter, Christoph A et al. (2009) Expression of ABCC-type nucleotide exporters in blasts of adult acute myeloid leukemia: relation to long-term survival. Clin Cancer Res 15:1762-9
Rao, Anuradha; Haywood, Jamie; Craddock, Ann L et al. (2008) The organic solute transporter alpha-beta, Ostalpha-Ostbeta, is essential for intestinal bile acid transport and homeostasis. Proc Natl Acad Sci U S A 105:3891-6
Honorat, Mylene; Mesnier, Aurelia; Vendrell, Julie et al. (2008) ABCC11 expression is regulated by estrogen in MCF7 cells, correlated with estrogen receptor alpha expression in postmenopausal breast tumors and overexpressed in tamoxifen-resistant breast cancer cells. Endocr Relat Cancer 15:125-38
Kruh, Gary D; Belinsky, Martin G; Gallo, James M et al. (2007) Physiological and pharmacological functions of Mrp2, Mrp3 and Mrp4 as determined from recent studies on gene-disrupted mice. Cancer Metastasis Rev 26:5-14
Belinsky, Martin G; Guo, Ping; Lee, Kun et al. (2007) Multidrug resistance protein 4 protects bone marrow, thymus, spleen, and intestine from nucleotide analogue-induced damage. Cancer Res 67:262-8

Showing the most recent 10 out of 28 publications