#multidrug resistance

Membrane Transportation

Which ABC transporter is associated with multidrug resistance in cancer?

Cancer multidrug efflux is dominated not by CFTR or P-type ATPases but by ABC transporters that expel amphipathic chemotherapeutics from cytoplasm. ABCB1 P-glycoprotein MDR1 is best studied, overexpressed in colonic, renal, adrenocortical carcinomas and after chemotherapy induction in leukemia, lymphoma and breast cancer. Its polyspecific hydrophobic binding chamber accommodates doxorubicin, daunorubicin, vinblastine, vincristine, paclitaxel and etoposide causing cross-resistance. ABCC1 MRP1 exports glutathione conjugates of drugs, ABCG2 BCRP expels mitoxantrone and topotecan. Expression corre

Ref: Gottesman et al., Annu Rev Med 2002, MDR in cancer; Szakacs et al., Nat Rev Drug Discov 2006.

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Membrane Transportation

The MDR1 (ABCB1) transporter is responsible for:

MDR1 officially ABCB1, also called P-glycoprotein P-gp, is a 1280 amino acid 170 kDa glycosylated plasma membrane exporter noted for conferring resistance to colchicine and doxorubicin in selection experiments. Tissue distribution includes apical brush border of small intestinal enterocytes limiting drug absorption, canalicular membrane of hepatocytes promoting biliary excretion, luminal membrane of proximal renal tubule mediating urinary elimination, endothelial cells of blood-brain barrier restricting central entry, and placental syncytiotrophoblast protecting fetus. Substrates are typically

Ref: Sharom, Pharmacogenomics 2008, P-glycoprotein; Alberts, 7th ed., Chapter 11 MDR transporters.

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Membrane Transportation

Which transporter is involved in multidrug resistance (MDR)?

Multidrug resistance in oncology frequently originates from increased efflux reducing intracellular drug accumulation below cytotoxic threshold. ATP-binding cassette transporters, particularly ABCB1 P-glycoprotein, ABCC1 MRP1 and ABCG2 BCRP, are major contributors. They are primary active pumps using two ATP hydrolysis events per cycle to switch transmembrane domains from high-affinity inward-facing to low-affinity outward-facing state, literally vacuuming hydrophobic substrates from inner membrane leaflet. Their drug-binding pocket is large, flexible and polyspecific, accommodating anthracycl

Ref: Gottesman et al., Nat Rev Cancer 2002, Multidrug resistance; Ambudkar et al., Annu Rev Pharmacol 1999.

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Cancer

Multidrug resistance in cancer commonly involves overexpression of

Over-expression of ATP-binding cassette transporters such as P-glycoprotein (encoded by MDR1) actively effluxes a wide range of hydrophobic drugs from the cytoplasm, reducing their intracellular concentration below the therapeutic threshold. This mechanism is a major cause of multidrug resistance in cancer chemotherapy. Inhibition of these pumps is therefore an active area of pharmacological research aimed at restoring drug sensitivity.

Ref: NCERT Biology Class 11–12 Alberts et al Molecular Biology of the Cell Lodish et al, Molecular Cell Biology Cooper & Hausman, The Cell Abbas et al., Cellular and Molecular Immunology (for immunology sections)

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