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Artículo destacado 
Drug News & Perspectives LOOKING AHEAD Together with the knowledge obtained on the molecular difference between cancer and normal cells, the understanding of membrane transport processes will facilitate the development of therapeutic strategies to prevent or circumvent resistance to treatment. Multidrug Resistance in Cancer: Its Mechanism and its Modulation by Ernest K.J. Pauwels, Paula Erba, Giuliano Mariani and Célia M.F. Gomes Summary One of the major problems related with the curative treatment of cancer patients is resistance against anticancer drugs. This resistance, which may occur from the beginning or is evident only later as an acquired phenomenon, is due to the action of drug transporters. These transmembrane proteins belong to the ATP-binding cassette (ABC) transporters which reduce bioavailability of drugs, but also determine the elimination of xenobiotics into bile, urine and feces. The present review summarizes recent knowledge in this area, highlighting the mechanism of action of these transporters, its clinical significance and its possible modulation. Novel approaches to overcome multidrug resistance include agents which inhibit or circumvent this efflux mechanism. For the latter category developments in nanomedicine may be of consequence. However, in spite of considerable progress in research regarding multidrug resistance, the phase of efficacious clinical use of this knowledge has not been reached yet. © 2007 Prous Science. All rights reserved. The tremendous developments in molecular biology and genetics in recent years have provided medical science with a new definition of disease. This is especially true for the development and progression of cancer. This disease is presently defined as an abnormal deviation from normal local biochemistry. Molecular derangements characterize this disorder in the very beginning, whereas at later stages tumor tissue may be detected as an anatomically measurable lesion by physical examination or by medical imaging. Cancer cells, as no other cells, have unstable mutable genomes leading to novel genetic configurations. The unbridled propensity to vary their genetic combinations originates from their instinct to survive and proliferate. New genetic variations may allow the cancer cells to escape from therapeutic intervention and restart their program of aggressive proliferation. In the clinical situation, it frequently occurs that tumors initially responsive to cytostatic drugs become resistant to this therapy. Their ability to develop ways to elude killing by cytostatic drugs is illustrated by their acquired ability to deploy new DNA repair mechanisms. Another very effective evasive maneuver is to bring into action pump mechanisms to transport drug molecules through the plasma membrane into the extracellular space. This strategy of excreting drugs is referred to as multidrug resistance (MDR) and involves cross-resistance to a large group of structurally diverse drugs with different modes of action. The mechanism for MDR is expression of the human MDR genes. This expression of MDR genes in a drug-sensitive cell is sufficient to produce a full spectrum of drug resistance. Another class of transporters, called multidrug-related proteins (MRPs), is encoded by MRP genes, which are quite distinct from MDR genes. Both types of proteins are members of the ATP-binding cassette (ABC) of transport proteins and transport substrates include both lipophilic and amphiphilic compounds. This article provides an overview of the biochemical mechanism of transporter-mediated drug resistance. We shall also focus on the clinical relevance of resistance to multiple chemotherapeutic agents. Finally, we will dwell on the possible modulation of this phenomenon. This overview will be preceded by a brief historic summary of the scientific discoveries providing insight into MDR. Historical perspective Over the last four decades, advances in the understanding of MDR in cancer went hand-in-hand with discoveries in many other biochemical fields. Therefore, the elucidation of the mechanism behind this issue results from the input from several groups (for an extensive summary of the timeline and scientific progress related to this subject see Ref. 1; part of the text below is extracted from this reference)1. In the early 1970s, it was found that Chinese hamster ovary (CHO) cells and variants thereof were resistant to colchicine (an antiinflammatory drug used for symptom relief in gout) and also to unrelated drugs such as daunorubicin and puromycin2. This phenomenon was ascribed to membrane alterations which led to the active outward transport of the drug3. The pleiotropic nature of this resistance suggested a more complex mechanism4, which was rejected as soon as the results of DNA transfer technology testing became available and pointed to the fact that MDR phenotypes are the result of a single gene mutation5. This resulted in a prominent protein present in the membrane of drug-resistant cells, which was called P-glycoprotein (P-gp), in which the term P stands for (colchicine)-permeability6. From experiments with isolated plasma membrane vesicles, it appeared likely that P-gp was an integral membrane protein7. Furthermore, the amount of this protein correlated with the level of colchicine resistance. The gene encoding for this protein was called the MDR gene. In fact, two kinds of MDR genes, termed MDR1 and MDR2, were found and the protein product of the MDR1 gene was P-gp8,9. Subsequently, it was shown that MDR1 was expressed in many epithelial cancers (liver, colon, kidney), hematopoietic cancers (leukemia, lymphoma) and solid tumors (breast, ovary)10. Based on these findings, it was postulated that P-gp had evolved as a general protein protecting vulnerable tissue from a wide range of circulating substrates, including drugs, pigments and metals ("xenobiotics"), creating barriers which were already known as the blood-brain barrier and the blood-ovary/testis barrier11. The major mechanism of protection appeared to be increased drug efflux12. The binding of ATP to P-gp13 and the presence of ATPase activity in P-gp-containing membranes14 provided evidence that P-gp was an energy-dependent transporter responsible for drug efflux in drug-resistant cancer. Once the role of P-gp as an efflux transporter was recognized, it appeared that various cells were able to expel xenobiotics in the absence of P-gp overexpression. This directed researchers to look for other transporters, and in 1992, Cole and co-workers observed the increased expression of a gene in a non-P-gp-expressing small cell lung carcinoma cell line.15 The drug pump encoded by this gene was baptized multidrug resistance-related protein (MRP). Like MDR1, MRP belongs to the ABC family of transporters responsible for drug (not necessarily anticancer drugs) transport out of the cell by using ATP as an energy source.16 In humans, about 50 ABC transporters have been discovered, of which 28 show evidence of drug extrusion.17 Classification and nomenclature The human genome contains 48 genes that encode ABC transporters and the members of the ABC family have 30-50% amino acid homologies among them. The superfamily of ABC transporters is divided into several subfamilies and classified on the basis of the sequence and structural organization of their binding domains18,19. There is a great deal of confusion with regard to the nomenclature of drug transporters. The authors of this article adhere to the listings and references provided in recent articles.20,21 For the sake of simplicity, we limited ourselves to summarizing the essential properties of the most extensively studied transporters. The currently known ABC family members have been compiled by Dr. Müller and the classification can be found at http:// nutrigene.4t.com, a website of Wageningen University, The Netherlands. The ABC transporter which appears to contribute most to MDR is P-gp (also known as MDR1), which is encoded by the ABCB1 gene in humans and the mdr1a and mdr1b genes in rodents. The sister protein of P-gp is ABCB11, a bile salt transporter also mediating paclitaxel resistance. Another member of this subfamily is ABCB4, which transports several cytotoxic drugs, such as paclitaxel and vinblastine. Whereas the ABCB transporters carry mainly cationic hydrophobic compounds, other subfamily members, categorized as ABCC transporters, extrude anionic compounds (e.g., methotrexate) and metabolic products. The ABCC1 (also known as MRP1) gene is widely expressed in cancer cells and exports anticancer drugs, as well as drugs conjugated to glutathione, glucuronate or sulfate22,23. Homologues of ABCC1 comprise ABCC2, ABCC3, ABCC6 and ABCC10, all known to be involved in resistance to antineoplastic drugs, although, at least for ABCC2, gene expression has not been found to be predictive of chemotherapeutic response in cancer. Furthermore, in contrast to ABCC1, the transporters ABCC3, ABCC6 and ABCC10 have only a limited involvement in clinically important drug resistance22,23. A different class of drug transporter is the ABCG subfamily. ABCG2 (also named MXR, ABC-P or BCRP) provides resistance to a variety of substrates, including mitoxantrone, daunorubicin, doxorubicin and camp- tothecins23,24. BCRP also interacts with synthetic tyrosine kinase inhibitors, such as imatinib, which has been proposed as a potent inhibitor of BCRP25. This transporter was discovered in a doxorubicin-resistant cancer cell line without overexpression of MDR1 or MRP126. The common names "breast cancer resistance protein" (BRCP) or "ABC transporter in placenta" (ABC-P) for ABCG2 illustrate the clinical relevance of this transporter. BCRP is expressed in a variety of normal tissues, with higher levels found in placenta and on the apical membranes of polarized cells in the intestine and liver. Enhanced expression in the placenta is consistent with the hypothesis of a protective role for BCRP on the fetus. BCRP expression has also been demonstrated in pluripotential side-population (SP) stem cells and possibly for the maintenance of the stem cell phenotype24. Separate from the family of ABC transporters is the "lung resistance-related protein" LRP, initially identified in a non-small lung cancer cell line resistant to anthracyclines.27 LRP is identified as a major vault protein and is localized in the cytoplasmic vesicles and on the nuclear membrane. Vault proteins appear to play a role in drug resistance by redistributing drugs away from their targets, such as the extrusion of cytostatics from the cell nucleus and/or sequestration into vesicles. In addition, it is to be expected that other transporters are active in drug export, providing resistance to conventional and more recently developed anticancer drugs. Biochemical structure and mechanism of action P-gp, encoded by the human ABCB1 gene, contains 1,280 amino acids and has a molecular weight of 170 kDa. P-gp has a transmembrane orientation (Fig. 1) and is comprised of 12 hydrophobic transmembrane domains (TMDs) and two hydrophilic nucleotide-binding domains (NBDs). The molecule consists of two similar halves separated by a short linker region. Domain 1 contains six segments, numbered TMD 1-6, which is followed by NBD 1. Domain 2 also contains six segments, named TMD 7-12, and is followed by NBD2. The hydrophilic region of P-gp contains the so-called ABC signature motif, or C motif, shared by all transporters of the large ABC superfamily. The ABC domains are involved in the transduction of energy provided by ATP hydrolysis, which enables the translocation (pumping) of P-gp transport substrates against the concentration gradient. The substrates which can be transported by P-gp strongly stimulate ATPase activity, which may be the basis of the fact that expression of P-gp is low in some tumors but is induced by chemotherapy28. The highly conserved signature of the ABC domains is essential for this action, as amino acid changes result in loss of ATPase activity.29,30 Moreover, defects in these transporters may cause inborn or acquired disease.31
Fig. 1. Schematic model of P-glycoprotein (after reference 32). The molecule has two homologous halves with transmembrane domains (TMDs). Each cylinder represents a transmembrane (TM) segment, involved in the formation of a drug-binding pocket. NBD, nucleotidebinding domain. Apparently, transporters do not provide a continuous channel that is present through the membrane. A proposed transport mechanism of P-gp was presented by Loo and Clarke.32 These authors highlighted a predicted transport cycle, based on their previous biochemical findings in the 1990s, in which transmembrane segments play a key role in the extrusion of a drug. In the absence of ATP or substrate, segments 6 and 10 are cross-linked. An added substrate, e.g., a drug, diffuses into the lipid bilayer and moves to a drug-binding pocket formed by segments 2, 5, 8 and 11. The structure of the drug-binding pocket affects the nucleotide-binding domains, which further inhibits ATP hydrolysis. The energy provided causes rearrangement of the drug-binding pocket and simultaneous efflux of the drug. Various drug substrates may enter the drug-binding pocket, but only binding in a particular orientation causes ATP hydrolysis and subsequent drug efflux, whereas other orientations do not result in removal of the xenobiotics. After this extrusion procedure, P-gp returns to its resting state, possibly with the involvement of further ATP hydrolysis (Fig. 2). In this model, the drug-binding pocket is funnel shaped and can be viewed as a relatively large chamber harboring one or possibly more dug molecules. This mechanistic model is often termed the "vacuum cleaner" model (another merely theoretical model is the "flippase" model, in which drugs are flipped from the inner leaflet to the outer leaflet by P-gp).
Fig. 2. Transmembrane domains (TMDs) of P-glycoprotein molecule, organized in such a way that a drug-binding pocket has been formed for extrusion of the xenobiotic (after reference 32). NBD, nucleotide-binding domain. As the pocket is basically formed by transmembrane segments, discrete mutations within these domains may influence the affinity of P-gp for the substrate. This probably explains why drug transport occurs for one drug and not for another, and why MDR is species-dependent. However, until the crystal structure of P-gp has been fully determined, the complete understanding of its mechanism of action remains uncertain. Clinical relevance The clinical impact of MDR in the effective treatment of cancer is difficult to underestimate. The issue represents a general challenge to almost all types of anticancer therapy. A redeeming feature is the fact that most resistance mechanisms are present in only a small fraction of each generation of cancer cell populations. Together with the above-mentioned drug specificity of the extrusion mechanism, the survival ability of tumor cell populations can be reduced by using two or three unrelated drugs simultaneously. Under such circumstances, the probability of acquiring resistance will be roughly equal to the square or cube of the probability of acquiring resistance to a single agent. Extensive preclinical and clinical studies on P-gp expression have demonstrated that most tumors displaying MDR can be divided into two classes: those in which P-gp expression is present in normal tissue and those in which P-gp expression is low or absent in normal tissue. As mentioned, P-gp expression in normal tissue is a way to protect these tissues from xenobiotics. It is normally expressed in human tissues, including the kidneys, adrenal cortex, liver, heart, jejunum and colon, brain, ovaries and testis, as well as in lymphocytes and hematopoietic bone marrow progenitor cells. In the brain, P-gp is expressed in the endothelial capillaries, thus playing an important role in the blood-brain barrier. P-gp is frequently low or absent in normal tissue of the lungs, ovaries and female breasts. When untreated tumors undergo chemotherapy, the P-gp level often increases, probably reflecting the induction of drug resistance due to epigenetic changes within the P-gp promoters33. A strong correlation between high levels of MDR protein expression and poor clinical outcome (e.g., event-free period, survival) has been reported for various malignances, including acute myeloid leukemia (AML)34, breast cancer35, testicular germ cell carcinoma36, ovarian cancer37, lung cancer38 and neuroblastoma39. Especially in articles dating from more than about 5 years ago, not all investigators found such correlations, most likely due to poor compilation of data and epidemiological study design. Moreover, MDR detection methods varied greatly from laboratory to laboratory due to lack of standardization. Modulation of MDR In view of the paramount role of MDR in antineoplastic chemotherapy, considerable efforts have been made to overcome the actions of the ubiquitous efflux pumps. P-gp inhibition has received the most attention by far and over time this research has resulted in the development and use of three distinct generations of modulators40. First-generation reversal agents comprised drugs already approved for other clinical applications, including calcium channel blockers (e.g., verapamil), immunosuppressive agents (e.g., ciclosporin) and steroids and antisteroids (e.g., progesterone and tamoxifen). However, it was found that these drugs were also substrates for efflux pumps and that their clinical effects were based on competition with the extrusion of the antineoplastic drug. Moreover, in general, these compounds were ineffective or toxic at the high concentrations required to block P-gp function41. Nevertheless, the usefulness of verapamil was clinically demonstrated, although serious cardiac toxicity due to high drug dose prevented its widespread use42,43. The second-generation agents to overcome MDR were designed to enhance the pharmacological profile by increasing their substrate specificity for the transporter families. These agents are derivatives of first-generation modulators lacking pharmacological effects. Examples include the cyclosporin D analogue PSC-833 (valspodar) and the (R)-enantiomer of verapamil (dexverapamil), which have selective and potent effects on P-gp activity without immunosuppressive properties or blockade of calcium channels, respectively44. However, every medal has two sides and more drastic modulation of these transporters lowered the ability of normal cells and tissues to protect themselves from anticancer drugs. It was clinically demonstrated that the longer circulation time of the cytostatic agents could damage organs such as the brain, normally protected by the blood-brain barrier, resulting in serious neurological disorders. Moreover, like many anticancer drugs, second-generation MDR modulators are metabolized by the cytochrome P-450 3A4 enzyme. The competition of the two drugs (after co-administration) can lead to unpredictable pharmacological consequences and will likely lead to a reduced clearance rate for the anticancer drugs via the biliary system and therefore clinically unacceptable plasma concentrations and toxicity45. PSC-833 has been studied in numerous clinical trials in combination with cytotoxic agents, albeit with little success due to unpredictable pharmacokinetic interactions that limited the metabolism and clearance of anticancer agents. A phase III trial in patients with AML was discontinued due an increase in morbidity and mortality in those patients receiving the inhibitor, probably due to toxic pharmacokinetic interactions46. The third-generation modulators have been designed specifically for high transport affinity and little pharmacokinetic interactions. These drugs bind with the structure of the nucleotide binding domain of P-gp in such a way that ATP hydrolysis is inhibited, inactivating the efflux mechanism. Novel drug development programs based on structure-activity relationship (SAR) studies conducted by the pharmacological industry have identified molecules which are efficient at nanomolar concentrations47. They were designed to offer significant improvements in chemotherapy, as dose reduction to overcome toxicity would not be necessary. In their review of these new drugs, Nobili et al48. highlight various clinical trials with these third-generation modulators (e.g., zosuquidar, elacridar and laniquidar) and mention the limited clinical improvements, stating that "the perfect reverser does not exist". Indeed, first reports on these third-generation drugs showed either varied or negative results not meeting the criteria for study expansion49,50. At present, various clinical trials are still ongoing. The approach whereby conventional anticancer chemotherapy is combined with MDR modulators still seems valid and efforts continue, although none of the methods has found general clinical use so far. The problems associated with MDR inhibition made researchers explore new ways which meant a radical departure from the above-mentioned approaches. One such approach is based on the principle that apoptosis in drug-sensitive cells enhances the efficacy of chemotherapy. In this context, it is interesting to note that ceramide acts as a second messenger in apoptotic signaling events51. The glycosylated form of ceramide, which results from elevated glucosylceramide synthase activity, was shown to accumulate in resistant tumor cells. The results of experiments in this field suggest that the stimulation of glycosylation is related to drug resistance by the inhibition of drug-induced apoptosis52. Therefore, blocking this elevated enzyme activity may enhance the proapoptotic action of ceramide53,54. In view of the considerable evidence indicating that glucosylceramide synthase contributes to drug resistance, inhibitory agents may well represent a novel and potential target for tumor therapy and be categorized as a "fourth generation" of MDR modulators. Another development worth mentioning concerns the use of a thiosemicarbazone derivative (NSC-73306) that induces selective cytotoxicity in cancer cells expressing P-gp55. This agent exploits P-gp function in such a way that MDR-positive cells become hypersensitive to this cytostatic compound in proportion to the increased P-gp function and resulting MDR. Interestingly, biochemical assays revealed no direct interaction between this novel agent and P-gp, which suggests that the physiological defense of normal cells and tissues remains undisturbed. Moreover, it appears that P-gp-expressing cells treated with NSC-73306 become sensitive to those P-gp substrates for which the cancer cells show resistance. Although the exact mechanism of action is still unknown and clinical efficacy needs to be proven, in vitro and ex vivo findings are encouraging for the treatment of tumors that are resistant to P-gp substrates. Concluding remarks Almost all of the highly conserved superfamily of ABC proteins function as active efflux pumps for a whole range of xenobiotics. These transporters are found in all types of organisms and help normal cells and tissues to survive in a toxic environment56,57. Mutations in the genes encoding for these transporters can cause a range of life-threatening genetic disorders, such as cystic fibrosis and adrenoleukodystrophy58,59. The other side of this protective mechanism is that cancer cells also use this efflux system, conferring tumor tissue resistance to chemotherapeutic agents and limiting the efficacy of clinical drug treatment in malignancies. Considerable progress has been made in the understanding of membrane transport processes. Together with the knowledge obtained on the molecular difference between cancer and normal cells, this will facilitate the development of therapeutic strategies to prevent or circumvent resistance to treatment. In this respect, the development of highly specific and potent efflux pump inhibitors is best achieved with structure-based drug design. These structural investigations offer the greatest opportunity to obtain the desired improved substrate specificity, reduced toxicity and kinetic features. It is clear that the battle to overcome clinical resistance in cancer treatment can only be won with a reversing agent that efficiently deals with resistance mechanisms specific for cancer cells, shows a lack of pharmacological interactions with other drugs and has a low cost/benefit ratio. It is probably unrealistic to expect that only one drug could tackle the whole assembly of transporters with all their slightly different molecular characteristics and biochemical mechanism. Therefore, attention has been paid to alternative research approaches, including genetic interventions to ablate transporters activity60 and the use of anticancer agents based on nanotechnologies61,62. All these efforts will eventually offer cancer patients a tailored combination of anticancer drugs with resistance reversal agents. The biggest challenge in this field is the design of MDR modulators which conserve normal tissue. Online links An animation for this article is available for subscribers to Drug News & Perspectives on-line supplement at journals.prous.com. Acknowledgments We gratefully thank Dr. Oliver Gell for critical reading of the manuscript. References 1. Gottesman, M.M. and Ling, V. The molecular basis of multidrug resistance in cancer: The early years of P-glycoprotein research. FEBS Lett 2006, 580: 998-1009. 2. Ling, V., Thompson, L.H. Reduced permeability in CHO cells as a mechanism of resistance to colchicine. J Cell Physiol 1974, 83:103-16. 3. Dano, K. Active outward transport of daunomycin in resistant Ehrlich ascites tumor cells. Biochim Biophys Acta 1973, 323: 466-83. 4. See, Y.P., Carlsen, S.A., Till, J.E. and Ling, V. Increased drug permeability in Chinese hamster ovary cells in the presence of cyanide. Biochim Biophys Acta 1974, 373: 242-52. 5. 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Kobayashi, T., Ishida, T., Okada, Y., Ise, S., Harashima, H. and Kiwada, H. Effect of transferrin receptor-targeted liposomal doxorubicin in P-glycoprotein-mediated drug resistant tumor cells. Int J Pharm 2007, 329: 94-102. Ernest K.J. Pauwels is Professor of Radiology, both at Leiden University, The Netherlands and Pisa University Medical School; Paula Erba is Associate Professor and Giuliano Mariani is Professor in the Department of Nuclear Medicine, University of Pisa Medical School; Célia M.F. Gomes is Associate Professor of Nuclear Medicine Research at the BiophysicsBiomathematics, IBILI, Coimbra University, Portugal. *Correspondence: E.K.J. Pauwels; E-mail: ernestpauwels@gmail.com. Drug News & Perspectives
Vol. 20, No. No. 6, 2007, pp. 371–377
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