Editing ABC transporter (section)

== Role in multi drug resistance ==

ABC transporters are known to play a crucial role in the development of [[multidrug resistance]] (MDR). In MDR, patients that are on medication eventually develop resistance not only to the drug they are taking but also to several different types of drugs. This is caused by several factors, one of which is increased expulsion of the drug from the cell by ABC transporters. For example, the ABCB1 protein ([[P-glycoprotein]]) functions in pumping tumor suppression drugs out of the cell. Pgp also called MDR1, ABCB1, is the prototype of ABC transporters and also the most extensively-studied gene. Pgp is known to transport organic cationic or neutral compounds. A few ABCC family members, also known as MRP,  have also been demonstrated to confer MDR to organic anion compounds. The most-studied member in ABCG family is ABCG2, also known as BCRP (breast cancer resistance protein) confer resistance to most Topoisomerase I or II inhibitors such as topotecan, irinotecan, and doxorubicin.

It is unclear exactly how these proteins can translocate such a wide variety of drugs, however, one model (the hydrophobic vacuum cleaner model) states that, in P-glycoprotein, the drugs are bound indiscriminately from the lipid phase based on their hydrophobicity.

The Discovery of the first eukaryotic ABC transporter protein came from studies on tumor cells and cultured cells that exhibited resistance to several drugs with unrelated chemical structures.  These cells were shown to express elevated levels of [[multidrug-resistance]] (MDR) transport protein which was originally called [[P-glycoprotein]] (P-gp), but it is also referred to as multidrug resistance protein 1 (MDR1) or ABCB1.  This protein uses [[ATP hydrolysis]], just like the other ABC transporters, to export a large variety of drugs from the cytosol to the extracellular medium.  In multidrug-resistant cells, the MDR1 gene is frequently amplified.  This results in a large overproduction of the MDR1 protein.  
The substrates of mammalian ABCB1 are primarily planar, lipid-soluble molecules with one or more positive charges.  All of these substrates compete with one another for transport, suggesting that they bind to the same or overlapping sites on the protein.   Many of the drugs that are transported out by ABCB1 are small, nonpolar drugs that diffuse across the [[extracellular medium]] into the cytosol, where they block various cellular functions.  Drugs such as colchicine and [[vinblastine]], which block assembly of microtubules, freely cross the membrane into the cytosol, but the export of these drugs by ABCB1 reduces their concentration in the cell.  Therefore, it takes a higher concentration of the drugs is required to kill the cells that express ABCB1 than those that do not express the gene.<ref name="Lodish_2012"/>

Other ABC transporters that contribute to multidrug resistance are [[ABCC1]] (MRP1) and [[ABCG2]] (breast cancer resistance protein).<ref name="pmid14530494">{{cite journal | vauthors = Leonard GD, Fojo T, Bates SE | title = The role of ABC transporters in clinical practice | journal = The Oncologist | volume = 8 | issue = 5 | pages = 411–24 | year = 2003 | pmid = 14530494 | doi = 10.1634/theoncologist.8-5-411 | s2cid = 2780630 | doi-access = free }}</ref>

To solve the problems associated with multidrug-resistance by MDR1, different types of drugs can be used or the ABC transporters themselves must be inhibited.  For other types of drugs to work, they must bypass the resistance mechanism, which is the ABC transporter.  To do this other anticancer drugs can be utilized such as alkylating drugs ([[cyclophosphamide]]), [[antimetabolite]]s ([[5-fluorouracil]]), and the anthracycline modified drugs ([[annamycin]] and [[doxorubicin]]-peptide).  These drugs would not function as a [[substrate (biochemistry)|substrate]] of ABC transporters, and would thus not be transported.  The other option is to use a combination of ABC inhibitory drugs and anticancer drugs at the same time.  This would reverse the resistance to the anticancer drugs so that they could function as intended. The substrates that reverse the resistance to anticancer drugs are called chemosensitizers.<ref name="Choi_2005"/>