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P-glycoprotein homologues

  • Chapter
Anticancer Drug Resistance

Part of the book series: Cancer Treatment and Research ((CTAR,volume 73))

Abstract

Multidrug resistance (MDR) is defined by the simultaneous acquisition of cellular resistance to a broad range of cytotoxic compounds bearing little or no structural and functional homologies [1–5]. MDR is caused in cultured cells in vitro [6–9] and in tumor cells in vivo [10–12] by the overexpression of P-glycoprotein (Pgp) (reviewed in [13]). The overexpression of Pgp in cultured cells leads to a decrease in intracellular accumulation of drugs concomitant with a commensurate increase in drug efflux, both strictly ATP dependent [13]. Pgp has been shown to bind photoactivatable analogues of ATP [14,15], and drug analogues [16-18], and has been demonstrated to possess ATPase activity [19]. These combined biochemical analyses have led to the proposition that Pgp functions as an ATP-driven drug efflux pump to reduce the intracellular accumulation of drugs in resistant cells. Pgp has been found to be encoded by a small family of closely related genes, designated mdr, which includes two members in humans (MDR1, MDR2) and three members in rodents (mdr1, mdr2, mdr3) for which full-length cDNA clones have been obtained [20–25]. Nucleotide and predicted amino acid sequence analyses of these clones indicate that they encode highly homologous proteins sharing the same length, between 70% and 85% sequence identity, and identical predicted secondary structures [20,22]. In the mouse, the prototype Pgp (1276 residues) is formed by two sequence homologous halves, each encoding six predicted membrane-spanning (™) domains and a nucleotide-binding (NB) fold.

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  1. Ellen Buschman
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Buschman, E., Lepage, P., Gros, P. (1994). P-glycoprotein homologues. In: Goldstein, L.J., Ozols, R.F. (eds) Anticancer Drug Resistance. Cancer Treatment and Research, vol 73. Springer, Boston, MA. https://doi.org/10.1007/978-1-4615-2632-2_2

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