The human multidrug resistance-associated protein (MRP) gene family: from biological function to drug molecular design.
The ATP-binding cassette transmembrane proteins play an important role in transport of drugs as well as of biologically active endogenous substances. The human multidrug resistance-associated protein (MRP) subfamily consists of at least six members, exhibiting a wide spectrum of biological functions. MRP1 operates as an ATP-dependent primary active transporter for substrates conjugated with glucuronide, sulfate or glutathione. Leukotriene C4 is an important endogenous substrate for MRP1. Glutathione serves as a cofactor in MRP1-mediated drug transport as well. Genes encoding both MRP1 and the catalytic subunit of gamma-glutamylcysteine synthetase (gamma-GCS) are coordinately regulated in cultured cancer cell lines as well as colorectal cancer tissues from colon cancer patients. The induction of MRP1 and gamma-GCS expression by oxidative stress varies among different cell lines, and p53 mutations are associated with elevated levels of induction. To modulate the transport function of MRP1, we have synthesized novel glutathione derivatives as photoreactive biochemical probes targeting the transporter protein. GIF-0019 restored the cellular sensitivity of MRP1-overexpressing drug-resistant cancer cells to anticancer prostaglandins in vitro, which was characterized by enhanced mRNA levels of the cyclin-dependent kinase inhibitor p21, suppressed c-myc expression and G1 arrest.
Ishikawa
T
T
Research Technology Development, Pfizer Pharmaceuticals Inc., Aichi, Japan. tishikaw@bio.titech.ac.jp
Kuo
M T
MT
Furuta
K
K
Suzuki
M
M
D018528:ATP-Binding Cassette Transporters / Q000235:genetics* / Q000378:metabolism*; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000627:therapeutic use*; D003110:Colonic Neoplasms / Q000235:genetics*; D015179:Colorectal Neoplasms / Q000235:genetics*; D015195:Drug Design; D018432:Drug Resistance, Multiple / Q000235:genetics*; D005721:Glutamate-Cysteine Ligase / Q000235:genetics; D006801:Humans; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D005810:Multigene Family; D014407:Tumor Cells, Cultured
D018528:ATP-Binding Cassette Transporters; D000970:Antineoplastic Agents; D005721:Glutamate-Cysteine Ligase; D027425:ATP-Binding Cassette, Sub-Family C Proteins