Multidrug-Resistance in Cancer: ABC-Transporters

Multidrug-resistance (MDR) is the chief limitation to the success of chemotherapy. According to the National Cancer Institute, multidrug-resistance is a phenomenon where cancer cells adopt to anti-tumor drugs in such a way that makes the drugs less effective. Studies have shown that 40% of all human cancers develop MDR. Deaths due to cancer occur in most of the cases when the tumor metastasizes. Chemotherapy is the only choice of treatment in metastatic cancer, and MDR limits that option.

Cancer one resized 600As shown in Figure 1, tumor cells adopt several mechanisms to evade death induced by anti-tumor agents. These include changes in apoptotic pathways and activation of cell-cycle check points to increase DNA repair. Alternatively, cancer cells develop resistance by increased expression of multidrug-resistant proteins and altered anti-tumor drug transport mechanisms. Members of the ABC transporters (ATP-binding cassette) are known to be associated with this phenomenon, as the human genome express over 48 genes in this transporter family alone. These proteins bind ATP in their ATP binding domain and use the energy to transport various molecules across the cell, thus they are known as ABC proteins. Among these proteins, P-glycoprotein (Pgp, ABCB1), multidrug resistance-associated protein (MRP1, ABCC1), and breast cancer resistance protein (BCRP, ABCG2) are chiefly responsible for drug resistance in tumor cells. Studies are warranted to determine the role of other members of ABC transporters including MRP2, MRP3, MRP4, MRP5, ABCA2 and BSEP in drug-resistance.

MDR1(Pgp)

cancerPlasma membrane glycoprotein (Pgp) was the first ABC-transporter detected in various cancers exerting resistance to a variety of chemically unrelated cytotoxic agents including anti-tumor drugs such as doxorubicin, vinblastine, ritonavir, indinavir and paclitaxel. It works as an energy-dependent efflux pump and can recognize a wide range of substrates. Even though this protein normally protects us from endogenous and exogenous toxins by transporting them out of the cells, the transporter causes a major problem in the bioavailability of anti-tumor drugs to tumor cells during chemotherapy.

Clinical Significance

Pgp plays an important role in altering the pharmacokinetics of a wide variety of drugs. This efflux pump creates a major physiological barrier in pharmacokinetics of drugs because of its localization at the site of drug absorption and elimination. Tumors with detectable levels of Pgp are 3-4 fold more susceptible to chemotherapeutic failure than Pgp negative tumors. Therefore the role of Pgp in the development of MDR is very significant: it has been used as a potential target for reversing clinical MDR. To overcome Pgp mediated drug resistance several inhibitors are developed and currently in clinical trials which include verapamil, cyclosporin A, quinine, and tamoxifen.

Multidrug Resistance Protein 1 (MRP1)

Like Pgp, MRP1 is also overexpressed in tumor cells and represents a major obstacle to drug delivery. MRP1 is ubiquitiously expressed in the lung, testis, kidney, and peripheral blood mononuclear cells in humans.

Clinical Significance

High levels of expression of MRP1 protein was observed in non-small-cell lung cancer. In breast cancer, there is also a significant expression of this protein which may increase the chance of treatment failure. Studies have also shown that over expression of MRP causes resistance to methotrexate (MTX) and antifoliates such as ZD1694 in colorectal cancer. Development of MRP1 inhibitors is in progress. In preclinical studies, effective inhibition of MRP1 was observed following treatment with MK571 and ethacrynicacid.

Breast Cancer Resistance Protein (BCRP)

BCRP belongs to a novel branch of the ABC-transporter family. The members of this subfamily are about half the size of the full-length ABC transporters, thus known as half-transporters. Overexpression of BCRP was reported in the plasma membrane of  drug-resistant ovary, breast, colon, gastric cancer, and fibrosarcoma cell lines. Even though the normal physiological function of BCRP has not been determined, it is possible that BCRP plays an important role in drug disposition. The overexpression of this protein causes reduced accumulation of chemotherapeutic agents such as mitoxantrone, irinotecan, SN-38, topotectan, and flavopiridol.

Clinical Significance

Since BCRP is expressed in the gastrointestinal tract, it is thought that this protein may affect the bioavailability of the drugs. Its overexpression in several types of cancer makes it a relevant target of strategies aimed at defeating multidrug-resistance. Some of the potent inhibitors of BCRP are Fumitremorgin C, reserpine and tryprostatin A.

Cancer defends itself against chemotherapeutic regimes by several mechanisms including MDR. Therefore, a detail understanding of ABC-transporters mediated drug resistance would help to formulate strategies to overcome this problem. Screening of novel inhibitors of ABC-transporters which are not effluxed by these transporters is currently in progress. One of these drugs, ixabepilone, has been approved in the United States for the treatment of breast cancer patients pretreated with an anti-tumor agent. Ongoing efforts to circumvent MDR also include development of potentially effective alternative strategies (e.g drug delivery using liposomes or nanoparticles, inhibition of expression of MDR associated ABC-transporters using monoclonal antibodies). Promising experimental data on these strategies suggest their potentialily to overcome important causes of MDR to significantly improve cancer treatment.

 

References:

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3.         Gottesman MM, Fojo T, Bates SE. Multidrug resistance in cancer: role of ATP-dependent transporters. Nat Rev Cancer. 2002;2(1):48-58.

4.         Gottesman MM, Ludwig J, Xia D, Szakács G. Defeating drug resistance in cancer. Discov Med. 2006;6(31):18-23.

5.         Nobili S, Landini I, Mazzei T, Mini E. Overcoming tumor multidrug resistance using drugs able to evade P-glycoprotein or to exploit its expression. Med Res Rev. 2012;32(6):1220-1262.

About Arup Chakraborty

Arup Chakraborty is postdoctoral research fellow at the National Cancer Institute, Bethesda, MD. He earned a doctoral degree from Texas Tech University, and his primary research interest is in the field of clinical cancer mainly in mechanisms of resistance to molecularly targeted therapies