Molecular analysis of the multidrug transporter, P-glycoprotein

Abstract

Inherent or acquired resistance of tumor cells to cytotoxic drugs represents a major limitation to the successful chemotherapeutic treatment of cancer. During the past three decades dramatic progress has been made in the understanding of the molecular basis of this phenomenon. Analyses of drug-selected tumor cells which exhibit simultaneous resistance to structurally unrelated anti-cancer drugs have led to the discovery of the human MDR1 gene product, P-glycoprotein, as one of the mechanisms responsible for multidrug resistance. Overexpression of this 170 kDa N-glycosylated plasma membrane protein in mammalian cells has been associated with ATPdependent reduced drug accumulation, suggesting that P-glycoprotein may act as an energy-dependent drug efflux pump. P-glycoprotein consists of two highly homologous halves each of which contains a transmembrane domain and an ATP binding fold. This overall architecture is characteristic for members of the ATP-binding cassette or ABC superfamily of transporters. Cell biological, molecular genetic and biochemical approaches have been used for structure-function studies of P-glycoprotein and analysis of its mechanism of action. This review summarizes the current status of knowledge on the domain organization, topology and higher order structure of P-glycoprotein, the location of drug-and ATP binding sites within P-glycoprotein, its ATPase and drug transport activities, its possible functions as an ion channel, ATP channel and lipid transporter, its potential role in cholesterol biosynthesis, and the effects of phosphorylation on P-glycoprotein activity.

Downregulation of caveolin-1 increases the sensitivity of drug-resistant colorectal cancer HCT116 cells to 5-fluorouracil

“…Chemotherapy is the alternative therapy strategy (30). However, the development of resistance during treatment limits the effectiveness of chemotherapy, as tumor cells may not only obtain resistance to the drug originally used, but may also exhibit cross-resistance to other drugs, which may be triggered possibly by multiple factors with different mechanisms (31)(32)(33). Thus, exploring the mechanism of chemoresistance is important to improve cancer treatment.…”

Functioning of an ABC transporter, Mdr49, in Hh signaling and germ cell migration

“…There are also many other fly ABC transporters, including MRP (33%), CG4562 (32%), CG31789 (32%) and White (32%) that share more homology with Ste6p than Mdr49. The only known PGC attractant, Hh, is probably far too large to be translocated through the SGP membrane via an ABC transporter (Germann and Chambers, 1998). Moreover, the two known lipid modifications of Hh, namely cholesterol and palmitate, are not isoprenoids.…”

MDR1 gene expression in endometrial carcinoma

“…This overall architecture is characteristic for members of the ATP-binding cassette or ABC superfamily of transporters. P-glycoprotein is often a significant barrier to oral absorption of chemotherapeutics at the intestine and also protects the liver, brain, placenta, testes, adrenal gland, and other tissues from cytotoxic insult (3) . P-glycoprotein is considered one of the most important members of the rapidly growing superfamily of integral proteins known as the ATP-binding cassette, which in humans also includes several other multidrug resistance membrane proteins, ie, MRP, the product of the cystic fibrosis gene, the TAP-1/TAP2 peptide transporters encoded by the major histocompatibility complex genes, and the gene encoding for breast cancer resistance protein (BCRP), also known as MXR1 (mitoxantrone resistance protein).…”