Homology between P-glycoprotein and a bacterial haemolysin transport protein suggests a model for multidrug resistance

Abstract

Increased expression of P-glycoprotein, a plasma membrane glycoprotein of relative molecular mass (Mr) 170,000 (170K), occurs in a wide variety of cell lines that exhibit pleiotropic resistance to unrelated drugs. The presence of P-glycoprotein in human cancers refractory to chemotherapy suggests that tumour cells with multidrug resistance can arise during malignant progression. We have discovered striking homology between P-glycoprotein and the HlyB protein, a 66K Escherichia coli membrane protein required for the export of haemolysin (protein of Mr 107K). P-glycoprotein can be viewed as a tandem duplication of the HlyB protein. The hydropathy profiles of the two proteins are similar and reveal an extensive transmembrane region resembling those found in pore-forming plasma membrane proteins. The C-terminal region of P-glycoprotein and the HlyB protein contain sequences homologous to the nucleotide-binding domains of a group of closely related bacterial ATP-binding proteins. We propose a model for multidrug resistance in which P-glycoprotein functions as an energy-dependent export pump to reduce intracellular levels of anticancer drugs.

A P-glycoprotein protects Caenorhabditis elegans against natural toxins

“…We determined the effect of the drugs emetine, ivermectin, chloroquine and colchicine on nematode development. Most of these compounds are known substrates for specific P-glycoproteins in other organisms (Gerlach et al, 1986;Samuelson et al, 1990;Schinkel et al, 1994;van Es et al, 1994). Deletion of the pgp-3 gene resulted in increased sensitivity to two drugs: colchicine and chloroquine.…”

“…Colchicine and chloroquine are structurally unrelated agents with dissimilar mechanisms of action. Colchicine, a major alkaloid derived from Colchicum autumnale L., acts on microtubuli and inhibits mitotic spindle formation and the secretion of glycoproteins (Gerlach et al, 1986;Budavari, 1989). This drug is included in the MDR spectrum of mammalian cells.…”

Elevated expression of Annexin II (Lipocortin II, p36) in a multidrug resistant small cell lung cancer cell line

“…Monoclonal antibodies against P-glycoprotein have facilitated the identification and characterisation of the genes involved in P-glycoprotein-mediated drug resistance (Riordan et al, 1985) and are playing an important role in elucidating the functional significance of this protein in clinical drug resistance (Gerlach et al, 1986). Similarly, the production of MAbs against antigens overexpressed in H69AR cells seemed an approach likely to provide useful tools for investigations of non-P-glycoprotein-mediated multidrug resistance.…”

The effect of hyperthermia in combination with melphalan on drug-sensitive and drug-resistant CHO cells in vitro

“…It has been shown that the acquisition of resistance to one cytotoxic drug may confer cross resistance to several other chemotherapeutic agents and that this pleiotropic drug resistance is frequently associated with increased expression of a 170,000 dalton glycoprotein (p-glycoprotein) (Center, 1983;Louie et al, 1986;Riordan & Ling, 1979). There is good evidence that p-glycoprotein is part of a cellular export system which increases drug efflux by an energy dependent mechanism (Center, 1983;Dano, 1973;Gerlach et al, 1986;Inaba et al, 1979;Skovsgaard, 1978), although reduction in intracellular drug levels alone is insufficient to account for the level of resistance observed in some systems (Bates et al, 1985a). It has previously been shown that influx of several chemotherapeutic agents is increased at elevated temperatures (Bates & Mackillop, 1986;Hahn, 1979;Nagaoka et al, 1986) and we have therefore explored the possibility that hyperthermia might be capable of overcoming the type of pleiotropic drug resistance which is associated with increased drug efflux.…”