Effective treatment of metastatic cancers usually requires the use of toxic chemotherapy. In most cases, multiple drugs are used, as resistance to single agents occurs almost universally. For this reason, elucidation of mechanisms that confer simultaneous resistance to different drugs with different targets and chemical structures - multidrug resistance - has been a major goal of cancer biologists during the past 35 years. Here, we review the most common of these mechanisms, one that relies on drug efflux from cancer cells mediated by ATP-binding cassette (ABC) transporters. We describe various approaches to combating multidrug-resistant cancer, including the development of drugs that engage, evade or exploit efflux by ABC transporters.

Targeting multidrug resistance in cancer

Fluorine in medicinal chemistry: A review of anti-cancer agents

Three ATP-binding cassette (ABC)-superfamily multidrug efflux pumps are known to be responsible for chemoresistance; P-glycoprotein (ABCB1), MRP1 (ABCC1) and ABCG2 (BCRP). These transporters play an important role in normal physiology by protecting tissues from toxic xenobiotics and endogenous metabolites. Hydrophobic amphipathic compounds, including many clinically used drugs, interact with the substrate-binding pocket of these proteins via flexible hydrophobic and H-bonding interactions. These efflux pumps are expressed in many human tumors, where they likely contribute to resistance to chemotherapy treatment. However, the use of efflux-pump modulators in clinical cancer treatment has proved disappointing. Single nucleotide polymorphisms in ABC drug-efflux pumps may play a role in responses to drug therapy and disease susceptibility. The effect of various genotypes and haplotypes on the expression and function of these proteins is not yet clear, and their true impact remains controversial.

ABC multidrug transporters: structure, function and role in chemoresistance

3.2. Other Potential in vivo Functions of Pgp 2992 3.3. Physiological Role of ABCG2 2992 3.4. Physiological Role of MRP1 2992 4. Structure of ABC Superfamily Drug Efflux Pumps 2992 4.1. Domain Structure of ABC Proteins 2992 4.2. Structure of Entire Bacterial ABC Proteins 2993 4.3. Structure of Pgp, MRP1, and ABCG2 2994 5. Substrate Specificity of ABC Drug Efflux Pumps 2995 5.1. MDR Spectrum Substrates 2995 5.2. Binding and Transport of Drugs 2998 5.3. Multidrug-Binding Pockets 2998 6. Catalytic Cycle of ABC Drug Efflux Pumps 3000 6.1. ATP Binding and Hydrolysis 3000 6.2. Occluded Nucleotide Conformation of Pgp 3000 6.3. Role of NBD Dimerization and the Occluded Conformation in the Catalytic Cycle of Pgp 3000

ABC efflux pump-based resistance to chemotherapy drugs.

Nanotechnology-based combinational drug delivery: an emerging approach for cancer therapy

Multidrug resistance reversal agents.

Multidrug Resistance Reversal Agents

The present invention concerns novel compounds having the structure (I) Another object of the invention is the use of compounds (I) for the fabrication of a medicament which is used for the treatment of tumour diseases

Christian Jarry

Papers

Multidrug resistance reversal agents.

Multidrug Resistance Reversal Agents

Bis [o-(14-benzoylaconine-8-yl)] esters