P-glycoprotein

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The P-glycoprotein is part of the ABC superfamily and is involved in drug efflux and therefore multi-drug resistance. The ABC superfamily can be divided into seven subfamilies, P-glycoprotein being a member of the subfamily MDR/TAP [1]. P-glycoprotein can be inhibited by cyclosporine A and verapamil.

P-glycoportein is expessed on the apical membrane of epithelial cells in the gut and has beneficial activity. Toxins from the gastraintestinal lumen diffuse into the epithelial cells but the toxins are transported out of the epithelial cells to prevents dangerous toxins reaching the blood stream.

P-glycoprotein is composed of 1280 amino acids arranged into 12 transmembrane strands which 2 nucleotide binding domains (NBDs). NBDs are ATP binding sites. 

P-glycoprotein causes a major problem with cancer chemotherapy resistance. P-glycoprotein has been linked to multidrug resistance, the phenomenon by which single-drug therapies select for cell lines expressing a high proportion of p-glycoprotein, resulting in initial remission, followed by regrowth of the tumour, now descended entirely from the high-P-glycoprotein cell lines. It is believed that inhibiting these transporters will increase the action and success of the chemotherapy drugs used [2]

Inhibiting p-glycoprotein has been an issue ever since it was discovered 35 years ago [3]. research has shown that thioxanthones have an antitumour activity and these combined with an amine, which is thought to have some P-glycoprotein inhibiting effects could possibly be the answer to chemotherapy drug resistance where p-glycoprotein is present [4][5][6].

References

  1. Reversion of resistance to immunosuppressive agents in three patients with psoriatic arthritis by cyclosporine A. Andrea Picchianti Diamanti. 2010. PubMed.
  2. Biochem Pharmacol. 2011 Oct 22, from the Epublication ahead of print. Dual inhibitors of P-glycoprotein and tumour cell growth: (Re)discovering thioxanthones.
  3. Essays Biochem, 2011 Sep 7; 50(1): 209-32
  4. Biochem Pharmacol. 2011 Oct 22, from the Epublication ahead of print. Dual inhibitors of P-glycoprotein and tumour cell growth: (Re)discovering thioxanthones.
  5. Biochem Pharmacol. 2011 Oct 22, from the Epublication ahead of print. Dual inhibitors of P-glycoprotein and tumour cell growth: (Re)discovering thioxanthones.
  6. Essays Biochem. 2011 Sep 7;50(1):209-32.
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