The phenomenon of multi-drug resistance in the treatment of malignant tumors

Vtorushin S.V.1, Khristenko K.Y.1, Zavyalova M.V.1, Perelmuter V.M.1, Litviakov N.V.2, Denisov E.V.3, Dulesova A.Y.1, Cherdyntseva N.V.1

Summary. Multi-drug resistance (MDR) is a condition when there is broad cross-resistance of cells to various agents which are different in structure and effect. Modern perceptions on mechanisms of MDR development in malignant tumors have been considered, in particular, in tre­ating breast cancer. Physiological functions and contribution to MDR development of ABC-transporter protein families have been described. The role of activation of glutathione system enzymes and apoptosis-regulating proteins in MDR formation has been shown.

Submitted: June 28, 2014.
*Correspondence: E-mail:
Abbreviations used: BC — breast cancer; BCRP — breast cancer resistance protein; GSH — glutathione; GSTs — glutathione-S-transferases; MDR — multi-drug resistance; MRP — multidrug resistance-associated protein; NBD — nucleotide binding domain; Pgp — Р-glycoprotein; ТMD — transmembrane binding domain.

Modern approaches to treating malignant tumors differ in multimodality and integrity, besides, chemotherapy plays an important role among therapeutic methods.

This treatment option significantly loses its topicality due to the presence of multi-drug resistance (MDR) of tumor cells, as a result of this phenomenon about 90% of treatment cases by cytostatic drugs end up in failures [1]. The MDR phenomenon is a condition, when there is broad cross-resistance of cells to various agents which are different in structure and effect [2, 3]. MDR was first described by the research group of J.L. Biedler in 1970 in experiments with cultivated cells [2]. It was discovered that, when treating cell culture with one drug, a population may be formed which is simultaneously resistant to many other substances, that cells have never contacted (cross-resistance). MDR in vivo may both appear during treatment and precede it [4].

Identifying the MDR phenomenon in clinical setting is of special importance, since, to reach the cytostatic effect, one has to either change treatment regimens or carry out aggressive chemotherapy; such treatment doesn’t often end up in the necessary outcome and is frequently accompanied by severe complications [5, 6].

MDR is formed by several molecular mechanisms which work both independently and together with one another, however, usually some mechanism is dominant. In forming drug resistance the mechanism providing efflux of chemotherapeutic drugs from the cell comes to the forefront against the concentration gradient with ATP energy consumption, which leads to the intracellular drug level falling below therapeutic concentrations and which is supported by functioning of the ABC-transporter family proteins (ATP-Binding Cassette Transporters) [3, 4, 7–10].

The following mechanisms of MDR development are also topical: firstly, activation of the glutathione system enzymes, which provides tumor cell deto­xificating superactivity and promotes fast inactivation of the chemotherapeutic drug or absence of its activation; secondly, mutations of the p53 gene or activation of bcl-2 gene, which leads to apoptosis cessation in response to the cytostatic drug action [3, 4, 7].


АВС-transporters are a big family of specific transmembrane ATP-binding translocator proteins, carrying various low-molecular weight substrates, including sugars, aminoacids, proteins, metal ions and different hydrophobic compounds [11–14]. In 1993 the research group of M.J. Fath suggested classifying more than 300 proteins of this family into three main groups: eukaryotic transporters, bacterial importers and bacterial exporters [15]. About 50 ABC-proteins have been discovered in a human organism, however, to date it has been proved that genetic evolution of these transporters in vertebrata is still continuing [16]. Studying of the evolution and mutation of ABC-transporter genes is of great importance for modern science, since these proteins influence the functioning of many systems in the organism [11, 12, 16, 17]. Changes in the structure of genes which code transporters are the basis of various pathologies, including disorders in cholesterol and bilirubin metabolism, neurological disturbances, some hereditary diseases etc.; moreover, they lead to a failure in penetration of not only exogenous, but also natural anti-tumor compounds, which are analogues of nucleosides, antimetabolites and tyrosine kinase inhibitors, into the cell [11, 12, 17–19].

АВС-transporters are divided into 7 subfamilies marked as ABCA, ABCB, ABCC, ABCD, ABCE, ABCF and ABCG [13, 20]. The structure of all representatives of the family is quite conservative and is united under domain organization, containing various combinations of two functional subunits: transmembrane ­binding domain (ТMD) or MSD-transmembrane subunit, which consists of six helices, and nucleotid binding domain (NBD) — a subunit including two domains. NBD domains are called Walker A, it is bound to the phosphoric acid residual of the ATP molecule. The second domain — Walker B domain — contains asparagine acid and is bound to magnesium associated with nucleotides [13, 21–23]. All ABC-transporters are divided into full and half transporters according to their structure. Full transporters are characterized by the (TMD-NBD)2 structure and are located in the cell membrane. Transporters with the TMD-NBD structure are called half transporters; they are usually located in the intercellular membranes (lysosomal, mitochondrial membranes, endoplasmic reticulum), the only exception being the ABCG2 half protein (alias BCRP — breast cancer resistance protein), which can be also located in the cell membrane [23, 24].

Prokaryotic and eukaryotic proteins of this family are 30–40% homologous according to the NBD subunit structure, regardless of the transported substrates [22].

In terms of chemical mechanisms, broad substrate affinity of ABC-transporters hasn’t been explained for a long time. At present it is supposed that formation of the so-called “inner pocket” underlies the ABC transporter functioning [3, 22, 25]. Such mechanism has been first suggested by Neyfakh, who investigated the functioning of a small bacterium protein, which was named BmrR [26]. The researchers found out that, when binding this protein to the substrate, the alpha-helix of the ligand-binding domain, conta­ining negatively charged gluthamine residue, unwinds (thus, forming “the inner pocket”); after that positively-charged ligands bind to this residue.

In clinical oncology research of expression and activity of ABC-transporters is aimed at eliminating disorder in toxic xenobiotic metabolism in tumor cells, i.e., the MDR phenomenon. From this point of view it is topical to study not all transport proteins, since mutations in genes coding the ABCD subfamily proteins are the basis of solely hereditary peroxisomal diseases [23]. ABCE and ABCF subfamilies include proteins containing one set of TMD-NBD; they are located in intracellular membranes and are not involved in MDR development [17].

Nowadays the ABCA subfamily is the most studied one, however, despite the fact that it includes the biggest amount of human ABC-transporters — 12 representatives — ABCA2 is the only protein of the subfamily that contributes to development of MDR to chemothe­rapy [23, 27]. Overexpression of ABCA2 in tumor cells gives them resistance to estramustine — an alkylating agent used in chemotherapy of prostate cancer [28].

The ABCB, ABCC and ABCG subfamilies are of the greatest research interest in clinical oncology in terms of MDR development in breast cancer (BC). Contribution of these subfamilies to the development of resistance to chemotherapy has been proved for malignant tumors of various localization: lung cancer, colon cancer, bladder cancer, prostate cancer as well as in leukemia, myeloma and sarcomas [9, 13, 29–39]. Nowadays development of targeted drugs directed to selective inhibition of tumor ABC-transformers is an urgent task [40, 41].

The role of the ABCB subfamily in emergence of resistance to chemotherapy. The ABCB subfamily (another name for the MDR subfamily) includes 11 proteins. Its representatives may be both full transporters (ABCB1 or Pgp, ABCB4, ABCB11), located in the apical part of the cell membrane and half transporters (ABCB2, ABCB3, mitochondrial membrane transporters ABCB6, ABCB7, ABCB8 and ABCB10 as well as lysosomal membrane transporter ABCB9) [23].

The ABCB1 protein (Р-glycoprotein, Pgp) is a big transmembrane protein with the molecular weight of 170 kDa; it is the largest studied representative of the ABC-transporter family which is involved in developing resistance of tumor cells to chemotherapy. Since the interrelation between membrane transporter proteins and MDR was first demonstrated when stu­dying P-glycoprotein, MDR, determined by overexpression of the stated protein, is also called typical or classic [3]. The protein was discovered in the membrane of resistant cells in the research laboratory by the research group of Juliano and Ling in 1976 [42].

Human Pgp is coded by the MDR1 gene, located on the chromosome 7 (7q21.1); besides, resistance development may follow both a change in MDR1 gene expression and amplification of the genome part containing the MDR1 gene and five-six other genes coupled with it [43–45]. Mechanisms of resistance development were studied in some research on investigating specially selected resistant Cerb-1 and Cerb-2 sublines as well as the CHLV-79RJK line of Chinese hamster cells [43, 44].

The MDR1 gene has two promoter regions — lower and upper promoters; gene activity is mostly regulated by the lower promoter [46]. Transcription activity of MDR1 rises in response to different impacts, including the effect of chemotherapy drugs (also the ones that are not Pgp substrates) [47]. Moreover, MDR1 activity may be influenced by р53, ras, raf, RAR-alpha and RAR-beta genes (genes of retinoid acid receptors) [3, 48] as well as genes of с-fos and c-jun transfactors [3, 49]. Supposedly, protein kinase C, protein kinase A and other protein kinases also take part in regulation of Pgp activity [50]. Taking into account multi-activity of MDR1/Pgp, it may be concluded that this transport system is extremely necessary for normal cell functioning; that is why its regulation is more than once repeated [3].

Pgp is a polypeptide which consists of two similar parts. Each part includes six hydrophobic transmembrane regions which cross the cell membrane 12 times, thus, forming pores and canals, by means of which Pgp releases substances, using ATP hydrolysis ener­gy from two binding sites in NBD domains [3, 25]. When dyed by monoclonal antibodies, predominant ABCB1 loca­lization is found on the surface of the cell membrane; small amount of ABCB1 are located in the area of Golgi complex [3, 51].

Prominence of Pgp expression in different tissues is not even; high values are found in tissues which actively contact xenobiotics: liver, kidneys, mucous membranes of the large and small intestine, adrenal tissue, brain ca­pillary endothelium, testicles, placenta trophoblast [32]. Extremely low level of protein expression is also found in the lungs and epidermis cells. In the bone marrow CD34-positive cells express functionally active Pgp [50], then, as cells of the myeloid type become mature, the expression and functional activity of this protein gradually decrease [35]. Tumors originating from Pgp-expressing cells will have pre-existing MDR.

The physiological role of ABCB1 is to protect from xenobiotics and export of endogenous metabolites [52, 53]: presence of P-gp in the intestinal epithelium prevents toxic substances entering the organism; its expression in renal tubules and the canalicular membrane of hepatocytes ensures their elimination from the organism. Рgp is overexpressed in the epithelium of the brain choroid plexus, which indicates its role in forming the blood-brain barrier [54]. P-glycoprotein located in the placenta trophoblast not only plays a significant role in limiting the effect of drugs and toxins on the fetus, but it is also necessary for normal development of the placenta and for maintaining its physiological functions [52].

Pgp is to a different extent expressed in all types of tumors. Tumors that are characterized by overexpression of the MDR1 gene are carcinomas of the large intestine and kidneys, hepatomas, renal tubule cancer, pheochromocytomas. In adenocarcinomas of the lungs and testicles, BC and sarcomas emergence of acquired MDR has been proved, which is determined by a rise in Pgp expression during chemotherapy or which is associated with genomic instability of malignant cells [55–58].

Pgp enhances tumor resistance to taxanes, podophyllotoxins, alkaloids of plant origin, including vinca alkaloids, antracyclic antibiotics and other chemotherapy drugs. Besides, this protein ensures fast elimination of many other substances: ethydium bromide, fluorescent dyes, gramicidin D, puromycin etc. [3, 44].

Pgp-mediated MDR is characterized by a decrease in cell resistance to chemotherapy drugs under the effect of MDR modulators or inhibitors [59]. Inhibitors are membrane-active low molecular weight lipophilic substances similar in their chemical compositions: calcium channel blockers (CCB) (nifedipine, verapamil and its analogues), trifluoroperasine, quinine, representatives of the acridine group, indole alkaloids (including reserpine and yohimbine), some antibiotics (cephalosporin, gramicidin, puromycin) and other [1, 50, 60]. Highly-efficient inhibitors discovered in the last years are А PSC833 (the analogue of cyclosporine) and the carboxamide derivative GG918 [60].

One of the mechanisms of inhibitor action is competition with cytotoxic agents for binding to Рgp (for example, in case of verapamil). The problem lies in the fact, that all the above-mentioned MDR modulators have been discovered in experiments in vitro in cell cultures, their use in clinical practice is impossible at this stage. The research has shown that for the majority of inhibitors it failed to obtain the concentrations in blood of patients that are necessary to overcome drug resistance, since a rise in dose gives severe complications [60].

In recent years new therapeutic approaches have been actively searched, such as the use of monoclonal antibodies to Pgp as MDR modulators and regulation of ABCB1 expression with help of epigenetic modulators (for instance, inhibitors of histone deacetylases — HDACi); nowadays clinical trials are being carried out [56, 61].

The role of the ABCC family in emergence of resistance to chemotherapy. This group includes 13 representatives which are full transporters; the majority of them (АBCC1–6, 10, 11) are active transmitters of various organic anions in hydrophobic drugs, therefore, they are involved in MDR development [11, 12].

The ABCC7, ABCC8 and ABCC9 proteins don’t participate in MDR development, however, they perform important functions of sustaining normal cell metabolism. The ABCC7 protein (CFTR) functions as an anion channel; it regulates their flow in epithelium cells. In case of mutations in the gene coding this transporter, cystic fibrosis develops [11, 12]. The АBCC8 (SUR1) and АBCC9 (SUR2) proteins, which are receptors of sulfonylurea [62], regulate permeability of ATP-specific potassium channels (Kir 6.2 and Kir 6.1, respectively). Mutations in genes that code these proteins may serve a reason for decreased tolerance to glucose [63].

The thirteenth family representative — АBCC13 — was discovered most recently; it was cultivated from cells of the liver, fetus and placenta, and its structure and functions are yet to be studied [11, 12].

A group of the ABCC family proteins, which determine MDR development, is united under a common name — multidrug resistance-associated protein (MRP) and includes nine members. MRP are transporters of organic anions (except for MRP9, which function has not been identified yet); consequently, they transport anionic drugs, such as methotrexate, and neutral drugs conjugated to acid residues, such as glutathione, glu­curonate and sulfate. However, MRP1, MRP2, MRP3 may also cause resistance to neutral organic drugs, which don’t form conjugates to acid residues [11, 12, 33, 64].

Six main representatives of MRP proteins (MRP1–6) are divided into two groups. MRP1, MRP2, MRP3 and MRP6 have the external N-terminal domain (marked as TMD0), which Pgp lack. MRP4, MRP5 don’t have the TMD0 domain, the degree of similarity of these proteins to MRP1 is less than 40% [33]. Nevertheless, they are more homologous than P-gp or other classes of ABC-transporters. Besides, research has shown that TMD0 is not necessary for transport activity [65].

The most well-studied representatives of MRP are the ABCC1 and ABCC2 proteins. The ABCC1 protein or MRP1 was discovered in 1992 by Cole et al. in lung cancer cell lines resistant to doxorubicin [72]. It is a transmembrane protein located on the basola­teral cell surface. Preferable substrates for MRP1 are organic anions, i.e., drugs conjugated to glutathione, glucuronate or sulfate [31, 34]; it is one of the main transporters of glutathione conjugates [66]. It is a protein with the molecular weight of 190 kDa, which gene is located on the chromosome 16 (16p13.1). It has five transmembrane segments in MSD2 and four-six transmembrane segments in MSD3 [67, 68].

MRP1 is widely expressed in epithelial cells of the organism, including digestive, urogenital and respiratory systems, in endocrine glands and hematopoietic organs, including all peripheral blood cells, regardless of their differentiation [30, 33, 36, 39]. Some resear­chers consider overexpression of the protein in bronchial epithelium as one of the reasons for bronchial asthma development [36].

High expression level of this protein has been detected in many tumor cells in lung cancer, colon cancer, BC, bladder cancer, prostate cancer as well as in leukemia [30, 69–71]. MRP1 plays an important role in cell MDR to etoposide, antracyclic antibiotics, vinca-alkaloids, stibium and arsenium drugs [72] as well methotrexate [33, 73].

Nowadays effective and safe MRP1 modulators are being searched. As potential MRP inhibitors LTC4, LTD4 and S-decylglutathione [74] are considered along with organic acids, originally developed for suppression of uric acid transport: sulfinpyrazone, benxbromarone and probenecid [75].

The ABCC2 (MRP2, cMOAT, cMRP) protein was first discovered in the hepatocyte cell membrane; due to this fact it was named canalicular multispecific organic aniontransporter (cMOAT) [76]. MRP2 is a transporter of bilirubin glucuronides in bile; gene mutations or a decrease in expression of this protein are known as the Dubin — Johnson syndrome [77].

ABCC2 expression is also identified in cells of proximal kidney tubules and intestinal epithelium. The MRP2 gene is located on the chromosome 10 (10q24). According to its domain organization it resembles MRP1; it is also a transporter of substances conjuga­ted to glutathione, glucuronic and sulfuric acids [13].

At present active research is being carried out on studying the link between MRP2 expression and the course of BC. By the immunohistochemical analysis it has been shown that two types of ABCC2 proteins are identified: the one located in the cell membrane and tumor cell cytoplasm (ABCC2c) and the one located in nuclear envelope of atypical cells (ABCC2n). According to the research results it may be concluded that tumors with overexpression of the protein in both locations are characterized by a worse forecast. If the protein is located in the nuclear envelope, tumors have more aggressive clinical presentation of the di­sease compared to cases when ABCC2 are located on the cell membrane [29].

MRP2 may be the cause of tumor cell resistance to methotrexate, cisplatin, etoposide, doxorubicin, epirubicin, vincristine and mitoxantrone [29, 72, 78]. On the whole the range of resistance coincides with the one in MRP1 with one exception: MRP2 induces resistance to cisplatin, which is not observed in MRP1 [78, 79].

Now effective inhibitors of ABCC2 are being searched; though MRP1 and MRP2 have similar substrate specificity, MRP1 inhibitors are not necessarily effective with respect to MRP2; for example, sulfinpyrazone is applicable only for ABCC1 therapy [33].

АBCC3 (MRP3, MOAT-D, cMOAT-2, MLP-2) is also a transporter of organic anions; however, as opposed to MRP1 and MRP2, it prefers glucuronates to glutathione conjugates [45, 80]. The MRP3 gene is located on the chromosome 17 (17q21.3), it codes protein expressed in norm in the epithelium of the large and small intestine, hepatocytes, pancreas, adrenals and lungs [11, 12, 64].

When studying the cell culture and the histological material from patients with lung cancer, MRP3 expression determines a decrease in sensitivity to etoposide, doxorubicin, vincristine and cisplatin. In the meantime, no direct link between MRP3 overexpression and tumor prognosis has been observed [81]. These cells are also resistant to short-term effect of methotrexate [82].

АBCC4 (MRP4, MOAT-B) is a specific transporter of conjugates to phosphorous acid residues (analogues of nucleosides); but it can also transport glutathione, glucuronides and sulfates. The gene co­ding MRP4 is located on the chromosome 13 (13q32). The MRP4 structure differs from that of MRP1, MRP2 and MRP3 in the absence of the NH2-terminal domain MSD (TMD0) [79]. Schuetz et al. [83] have found out that MRP4 eliminates drugs for HIV treatment from the cell: 9-[2-(phosphono metoxi)ethyl]adenine (PMEA) and azidothymidine monophosphate (AZTMP) in cells that are resistant to PMEA. High level of MRP4 is also a reason for severe drug resistance of cells to some nucleoside analogues, including 9-[2-(phosphono metoxi)ethyl] guanine, which has antitumor activity. Moreover, tissues with MRP4 overexpression have short-term resistance to methotre­xate, as MRP3 [84]. Lai et al. have established that glutathione plays an important role in MRP4 functi­oning; depletion of its intracellular reserves decreases cell resistance to nucleoside analogues [85].

The gene coding ABCC5 (MRP5, MOAT-C, pABC11, sMRP) is located on the chromosome 3 (3q27), high expression of this transporter has been detected in many tissues of the organism, especially in the musculoskeletal system and in the brain [79]. Overexpression of MRP5 leads to resistance to thiopurines, such as 6-mercaptopurine and tioguanine, which are used to treat acute lymphoblastic leukemia and acute myeloid leucosis, and to PMEA [33]. McAleer et al. [86] also found that accumulation of anionic fluorochromes decreases in MRP5-transfected cells; they acquire resistance to heavy metals. Research has demonstrated that MRP5 may be inhibited by sulfopyrasone and benzbromarone [87].

The АВСС6 gene (MRP6, MOAT-E, MLP-1, ARA) is located on the chromosome 16 (16p13.1); high level of MRP6 expression has been detected in the liver on the lateral hepatocyte membrane and in the kidneys [82]. The physiological role of this protein is unclear. To date it has been known that deletions and other mutations in the gene, coding this protein, lead to development of pseudoxanthoma elasticum, a disease that is characterized by disorder in formation of yellow fibers accompanied by skin, eye and cardiovascular lesions [88].

Belinsky et al. [89] have analyzed the contribution of MRP6 to MDS: in MRP6-transfected cells low level of resistance to anthracyclic antibiotics and podophyllotoxins (etoposide, tenyposide) is observed.

Interestingly, overexpression or full/partial amplification of the MRP6 gene was found only in cell lines with MRP1 overexpression/amplification. It is likely that MRP6 doesn’t play a significant role in tumor cell resistance, and its expression together with MRP1 is explained by close proximity of their genes on the chromosome 16 [82, 90]. Amplification of 3-end of the MRP6 protein is of great importance in cell MDR of patients with acute myeloid leukemia; earlier this MRP6 region was called ARA (anthracycline resistance-associated protein) [91].

ABCC10 (MRP7) is a protein with the molecular weight of 158 kDa, coded by the gene located on the chromosome 6 (6p12–21). It has been discovered relatively recently in reticulocyte lisates; its extremely low expression was detected in other tissues as well; its physiological role is currently unknown [92].

ABCC11 or MRP 8 is a protein with the molecular weight of 150 kDa, which gene is located on the chromosome 16 (16q12.1). In normal tissues moderate protein expression is observed in the testicles and the liver. The MRP8 structure is close to that of MRP5: homology is 42% [93].

The research by Bera et al. [94] determined high level of MRP8 expression in tumor tissues of patients with BC. The MRP8 gene codes two different RNA transcripts: 4.5-kb and 4.1-kb. In the meantime, 4.5-kb transcript was detected in breast tumors, whereas 4.1-kb — in testicle cells. The physiological role and the contribution of this transporter to development of BC as well as resistance to pharmacotherapy is currently unknown [93, 94].

The ABCC12 (MRP9) protein was identified by two research groups — Bera et al. [94], Tammur et al. [93] — in tumor cells of patients with BC. The MRP9 gene, located on the chromosome 16 (16q11), also codes two different mRNA transcripts (4.5-kb and 1.3-kb transcripts), which are expressed in various tissues in a different way: 4.5-kb transcript was detected in tumor tissue in BC and in normal tissues of the breast and the testicles, whereas the 1.3-kb transcript was found in brain tissues, ske­letal muscles and testicles [95]. The physiological role of MRP9 and its contribution to MDR emergence are currently not determined.

The role of the ABCG family in emergence of resistance to chemotherapy. Five human proteins of this group are described; they are represented by half membrane transporters located in the cell membrane. This differentiates them from other half transporters situated in intracellular membranes [96].

It is proved that mutation of genes that code ABCG5 and ABCG8 leads to development of rare autosome-recessive pathology — р-sitosterolemia, which is characterized by accumulation of plant sterol in blood and tissues [97].

The main physiological role of the ABCG1 protein is support of lipidic homeostasis in organism tissues, especially in the lungs, central nervous system and vessels [96, 98–100]. Besides, this protein participates in secretion of insulin by pancreas β-cells [98, 100–102], controls proliferation of hematopoietic stem and multipotent precursor cells both in the bone marrow and spleen in case of extramedullary hematopoiesis [100, 103]. ABCG1 malfunction leads to development of atherosclerosis, excess accumulation of lipids in macrophages and formation of foam cells [98, 99, 104]. Mutations of the gene coding the ABCG1 protein are accompanied by risk of type II diabetes deve­lopment [101, 102]. The role of this protein in MDR development is unclear, however, in 2012 V. Hlaváč et al. compared breast tissue samples before and after neoadjuvant therapy and found out that after therapy expression of ABCG1 rises [105].

The ABCG2 protein has been described to the ful­lest extent, it is the only representative of the family, which overexpression is proved to cause MDR deve­lopment [96]. This protein was first discovered by the research group of L.A. Doyle in 1998, when studying the MCF-7 cell line of BC; it was named BCRP. The stated protein was also identified in other research, it has interchangeable names MXR (mitoxantrone resistance protein) and ABCP (placental ABC transporter) [106–110].

BCRP is a protein with the molecular weight of 72.6 kDa, its coding gene is located on the chromosome 4 (4q22) [111]. High expression of this protein is marked in the placenta, myocardium, testicles and endothelium of vessels [111, 112]. Medium level of expression is found in the liver, large and small intestine, brain and prostate; low expression during histochemical studies has been discovered in the lungs, skeletal muscles, pancreas, kidneys, spleen, thymus, multi-layered skin and esophagus epithelium and peripheral blood leukocytes [106, 112, 113].

Physiological functions of BCRP lie in providing tissue protection from endogenic toxins or xenobiotics and regulating cell homeostasis of physiologically important compounds such as heme, porphyrin, riboflavin and estrogens [114–116]. ABCG2 plays the key role in folic acid homeostasis, which may promote cell survival in conditions of hypoxia [108]. Besides, much research has shown that high expression of this protein is marked in primitive stem cells of human bone marrow, which ensures protection of these cells from xenobiotics [109].

Research of BCRP expression in normal tissues that was carried out by Doyle and Ross [113] proved an extremely high level of ABCG2 in the placenta (in particular, in syncytiotrophoblast and on the apical surface of chorionic villi) — about 100 times higher than in other tissues with high expression of this protein. This fact suggests that BCRP plays a particular role in protecting the fetus from toxic substances [52].

Many researchers believe that this transporter performs a protective function as part of the blood-brain barrier due to high expression in the endothelium of brain vessels [106–108, 117].

In tumor cell lines a high level of ABCG2 has been detected in BC, colon cancer, stomach and lung cancer, myeloma and sarcomas [13, 118–120]. ABCG2 of mRNA has also been identified in blast cells of patients with acute myeloid leukemia resistant to chemotherapy [121, 122].

It has been proved that overexpression of BCRP promotes resistance of tumor cells to mitoxantrone, antracyclic antibiotics (in particular, doxorubicin), methotre­xate, camptothecin derivatives (topotecan, SN-38) and indolocarbazole derivatives. In the meantime, resistance to antracyclic antibiotics is unstable and is probably connected with the presence of mutation in the 482 codon of the gene coding BCRP [109, 113, 123–126].

At present effective specific inhibitors of BCRP are being searched, the influence of tyrosine kinase inhibitors as well as a number of antiviral drugs, used for HIV treatment, statins and imatinib on the transporter function is studied [106, 109, 124]. At the moment a whole class of new compounds synthesized from XR9576 (tariquidar) has been received, which selectively inhibit BCRP [110].


Glutathione (GSH) is a tripeptide which is synthesized in the organism from glutamic acid, cycteine and glycin; it performs detoxificating, antioxidant and immunoprotective functions. The action of glutathione is ensured (carried out) by its conjugation in various electrophilic substances; this process is catalyzed by glutathione-S-transferases (GSTs) [127, 128].

GSTs are found in all mammals and plants. They may exist as homo- and heterodimers with the molecular weight of 43–57 kDa, each subunit has its own independent binding site, which, in turn, contains two subsites: G and H. The former interacts with glutathione (contains protein –SH group, histidine and arginine); the latter binds the hydrophobic substrate, it contains glycine. According to identity of the aminoacid composition, GSTs in mammals are grouped in six classes: α- (alpha-), μ- (mu-), κ- (kappa-), θ- (theta-), π- (pi-) and σ- (sigma-) GST. In human organism mostly four main GST classes are expressed: GSTA (α-class), GSTM (μ-class), GSTT(θ-class) and GSTP(π-class) [127, 129]. Glutathione transferases are mainly located in the cytosol and endoplasmic reticulum, however, they may be found in nuclei and mitochondria as well.

Representatives of the GSTA class are widely expressed almost in all tissues of the organism; they are the main representatives of glutathione transferases in the liver. The GSTM class includes five genes with different expression localization: GSTM1 is expressed in blood and liver cells, GSTM2 — solely in muscles, GSTM3 and GSTM4 — in cells of the central nervous system, GSTM5 — in cells of the central nervous system, liver, testicles and to a smaller extent — in transverse cardiac muscles. Glutathione transferases of the theta-class are located in erythrocytes and cells of the liver. The GSTP class, as the only representative of GSTP1, is also widely spread in cells of the orga­nism as well as alpha-class representatives, but it lacks in erythrocytes; its highest expression is marked in cells of the placenta and skin [127, 129, 130].

Recently it has been discovered that the GSTs system not only promotes detoxification of xenobio­tics and cancer-inducing substances, but also acts as a modulator of the pathway which transmits signals that control cell proliferation and apoptosis [127, 130].

Multifunctional family of glutathione-S-transferase also plays an important role in catechol estrogen metabolism. In case of catechol estrogens GSTs act as a detoxificating agent, promoting conjugation of genotoxic estrogen metabolites to glutathione, which, as well as conjugation to N-acetylcycteine and cycteine, causes their inactivation [131–134]. In some research it has been shown that there is a link between GSTs gene polymorphism and risk of BC development. In the so-called zero genotype of GSTs, which is characterized by low enzyme activity, risk of BC development was 2.1 times higher in pre-menopausу and 2.5 times higher in post-menopause, and in case of zero genotype combined with low acti­vity of ca­techol-O-methyl transferase it was 3.5 times higher [132, 135].

Disorders in glutathione system metabolism in the human organism may be the cause of malignant tumor development. A rise in GSTs activity in tumor cells results in development of resistance to a number of chemotherapy drugs [136]. Thus, according to the carried out research, high concentration of glutathione has been detected in cell lines resistant to alkylating agents (embichine, chlorbutin, melphalan, cyclophosphamide etc.) and other drugs [3, 132, 137, 138].

The role of glutathione system activation in deve­lopment of drug-resistance was demonstrated when studying the level of GSH and GSTs in P 388 leukemia cells resistant to cycloplatam. The level of glutathione was almost 10 times higher compared to parent cells of this line, whereas glutathione transferase activity was 1.5 times higher in cells of the resistant strain as opposed to the sensitive one. Cycloplatam administered to tumor carrying mice has caused a significant increase in the level of GSH in tumor cells of both strains. The obtained results indicate that GSH-dependent enzymes may significantly contribute to drug resistance of cells [139]. Thus, the role of MDR development associated with glutathione transferase activation in brain tumors has been proved [140].

When studying changes in the glutathione system, emergence of resistance has been proved not only to alkylating agents, but also to antracyclic antibiotics and vincristine (drugs of Pgp-MDR), which suggests existence of general mechanisms of regulation of ABC-transporter genes and genes involved in glutathione metabolism [139].

The research group of C.S. Morrow [141] has shown that overexpression of PGP and a rise in GST acti­vity are identified in the MCF7 cell line of BC resistant to 4-nitroquinoline-1-oxide (4-NQO). In the meantime, such combination is associated with GST-dependent increase in formation of 4-NQO-glutathione-conjugates, which are eliminated from cells by Pgp [141, 142].

Many types of malignant tumors contain the increased amount of glutathione in tissues and have high activity of glutathione transferases, which allows their cells to increase resistance to chemotherapy right up to MDR formation. At present a number of drugs inhibiting GSTs selectively in tumor cells are being developed; their use in combination with cytostatic drugs should increase the efficiency of anti-tumor therapy. Inhibitors are also considered as one of the potential therapeutic approaches to treating other diseases related to aberrant cell proliferation [143, 144].


Nowadays the mechanism of MDR development related to apoptosis suppression is paid more and more attention to, since the cytostatic effect of the majority of drugs is realized by induction of this very pathway, regardless of a certain mechanism of action of every drug. The key role in apoptosis is played by functional activity of TP53 and bcl-2 genes as well as their protein products [7, 145–149].

Mutation of the ТР53 gene and development of the MDR phenomenon. During cell tumor transformation and tumor progression one of the most common changes is mutation of the TP53 tumor in the suppressor gene [150–152]. In norm the TP53 gene is activated in response to various cell damaging factors; in the meantime, the wild type of the p53 protein is synthesized, which leads to a stop of the cell cycle and (or) facilitates cells entering apoptosis [153, 154]. In defective cells conditions for damaged DNA reparation emerge, otherwise cells are removed from the population. Cells where normal p53 lacks are resistant to apoptosis induction [155]. The p53 mutagenic protein demonstrates the properties of an oncogene, since it doesn’t have the ability to stop cell division at the key points of the cell cycle, which results in the beginning of DNA replication in cells on the da­maged matrix. It promotes instability of the genome and development of malignant transformation [156, 157]. Therefore, tumor cells with mutant ТР53 are resistant to the action of alteration factors, which include cytostatic drugs [3, 158].

It has been proved that stromal cells of malignant epithelial tumors, in particular, fibroblasts with unchanged suppressor gene р53, are able to produce and secrete tumor inhibiting factors [159, 160].

Inductors causing the wild type of p53 are a combination of agents that cause DNA damage in different ways, for example, by changing the redox-potential (in particular, during accumulation of reactive oxygen species) or the nucleotide pool in the cell, which leads to destruction of the mitotic spindle of cell division etc. [153, 161]. Due to this fact malignant tumors with the mutant р53 are typically resistant to drugs with diffe­rent mechanism of action (for instance, to cisplatin and 5-fluorouracil) [3].

There are also many facts proving that the p53 protein participates in regulation of ABCB1 action. It has been shown that the wild type of p53 suppresses and the mutant p53s protein increases ABCB1 activity [48, 56, 158]. Besides, when studying MDR of rhabdomyosarcoma and neuroblastoma cell lines, it has been found out that p53 is a strong inhibitor of P-glycoprotein and ABCC1 (MRP1) functions [56, 57]. When studying MDR of prostate cancer, the correlation between a decrease in the degree of tumor differentiation and a rise in MRP1 expression has been identified. A combination of these two mechanisms resulted in development of tumor resistance to doxorubicin and vinblastine [57, 162, 163].

Therefore, functional recovery of the wild type of p53 may be the strategy for reducing or preventing MDR; it may also help increase sensitization of cancer cells to anti-tumor drugs [56, 153, 154, 164, 165].

The Bcl family of proteins and its influence on emergence of resistance to chemotherapy. Besides tumor suppressors, malignant tumor sensiti­vity to various xenobiotics is influenced by antiapoptotic proteins. The leading role in this process is given to the Bcl family proteins [166]. Functions of proteins of this family are directly opposite to one another; the bcl-2 gene codes proteins having both antiapoptotic (BCD-XL, Bag, Bcl-2) and proapoptotic (Bcl-xS, Bax, Bad, Bak, Bid) effects on cells [133, 167, 168].

It was proved that during Bcl-2 overexpression tumor cells have drug resistance to various cytostatic drugs [169]. There are data indicating that expression of the bcl-2 gene may be referred to markers of drug resistance to chemotherapy in a number of malignant tumors: bladder cancer, prostate cancer, testicular cancer, myeloid and lymphoid tumors of the hematopoietic system, brain tumors [130, 170, 171].

Clinical studies have detected the interrelation between the expression level of antiapoptotic genes bcl-2 and bcl-xL in various tumors and their high resistance to chemotherapy drugs [172, 173]. However, in lung and BC one can’t say for sure about the correlation between bcl-2 overexpression and resistance to chemotherapy, since expression of antiapoptotic proteins Вс1–2 and Bcl-xL occurs in cells of these tumors alongside with expression of the Bax proapoptotic protein [145, 173–177]. The Вс1–2 and Вах proteins form heterodimers inactivating the action of the antioncogene; consequently, the proportion of these proteins in the cell determines its predisposition to apoptosis and chemotherapy drug action [145, 176]. In the work by Sumantran et al. intensification of induced apoptosis has been detected in the transfected cell line of BC MCF-7 in response to etoposide and taxol [178]. According to the latest research, overexpression of Bcl-2 that occurred after first-line chemotherapy of BC suggests MDR development in response to therapy [55, 173, 179, 180].

Proapoptotic proteins bcl-2 have a domain in their structure called BH3, its binding by antiapoptotic proteins bcl-2 leads to apoptosis suppression [181]. Compounds that inhibit this bound induce apoptosis on their own or in synergism with other cytostatic chemotherapy drugs. Recently a whole range of such drugs has been developed, however, further research has shown that many assumed inhibitors are not specific and have other cell targets [181–184]. There are two exceptions to this: for instance, ABT-737, its successful application as the only drug agent for treatment of leukemia and lung cancer has been proved. The second drug is ABT-263; at present it is at the stage of clinical trials for treating small-cell lung cancer, lymphatic leukemia and lymphoma [185, 186].

In conclusion it should be said that disorder in regulation of genes that are involved in apoptosis control (oncosuppressor р53 and genes of the bcl-2 family) may lead to cells developing resistance to a wide range of anti-tumor drugs — DNA-tropic agents (adriamycin, actinomycin D), antimetabolites (5-fluorouracil), but not to the compounds interacting with mitotic spindle of cell division (colchicine, taxole) [187–191].


Nowadays one of the leading methods of treating malignant tumors is chemotherapy, both non-adjuvant and adjuvant. This therapy is significantly losing its topicality due to the presence and (or) development of MDR. In the mechanism of MDR development activation of ABC-transporter proteins and glutathione system enzymes as well as changes in apoptosis-controlling genes plays the key role. Therefore, determination of MDR marker expression in malignant tumors will allow to assess the rationality of chemotherapy prescription and correct the treatment strategy. Due to this fact it is topical to study markers of MDR depending on the morphological structure and molecular-genetic cha­racteristics of the primary tumor.


The study is supported by the grants № 14–04–31727/14 and № 13–04–98111 r_Sibir_a of Russian Foundation of Basic Research (RFBR) and Grant of the President of the Russian Federation (agreement


1. Pluchino KM, Hall MD, Goldsborough AS, et al. Colla­teral sensitivity as a strategy against cancer multidrug resistance. Drug Resist Updat 2012; 15: 98–105.
2. Biedler JL, Reihm H. Cellular resistance to actinomycin D in Chinese hamster cells in vitro: cross-resistance, radioautographic, and cytogenetic studies. Cancer Res 1970; 30: 1174–84.
3. Stavrovskaya AA. Cellular mechanisms of multidrug resistance of tumor cells. Biochemistry 2000; 65: 95–106.
4. Borst P. Genetic mechanisms of drug resistance. A review. Acta Oncol 1991; 30: 87–101.
5. Hernandez-Aya LF, Gonzalez-Angulo AM. Adjuvant systemic therapies in breast cancer. Surg Clin North Am 2013; 93: 473–91.
6. Bartlett J, Canney P, Campbell A, et al. ­Selecting breast cancer patients for chemotherapy: the opening of the UK OPTIMA trial. Clin Oncol (R Coll Radiol) 2013; 25: 109–16.
7. Baguley BC. Multiple drug resistance mechanisms in cancer. Mol Biotechnol 2010; 46: 308–16.
8. Coley HM. Mechanisms and strategies to overcome chemotherapy resistance in metastatic breast cancer. Cancer Treat Rev 2008; 34: 378–90.
9. Fukuda Y, Schuetz JD. ABC transporters and their role in nucleoside and nucleotide drug resistance. Biochem Pharmacol 2012; 83: 1073–83.
10. Wu CP, Hsieh CH, Wu YS. The emergence of drug transporter-mediated multidrug resistance to cancer chemotherapy. Mol Pharm 2011; 8: 1996–2011.
11. Dean M, Rzhetsky A, Allikmets R. The human ATP-bilding cassette (ABC) transporter superfamily. Genome Res 2001; 11: 1156–66.
12. Dean M, Hamon Y, Chimini G. The human ATP-binding cassette (ABC) transporter superfamily. J Lipid Res 2001; 42: 1007–17.
13. Lockhart AC, Tirona RG, Kim RB. Pharmacogenetics of ATP-binding cassette transporters in cancer and chemotherapy. Molecular Cancer Therapeutics 2003; 2: 685–98.
14. Silverton L, Dean M, Moitra K. Variation and evolution of the ABC transporter genes ABCB1, ABCC1, ABCG2, ABCG5 and ABCG8: implicationfor pharmacogenetics and disease. Drug Metabol Drug Interact 2011; 26: 169–79.
15. Fath MJ, Kotler R. ABC transporters: bacterial expor­ters. Microbiol Rev 1993; 57: 995–1017.
16. Moita K, Dean M. Evolution of ABC transporters by gene duplication and their role in human disease. Biol Chem 2011; 392: 29–37.
17. Klein I, Sarkadi B, Varadi A. An inventory of the human ABC proteins. Biochim Biophys Acta 1999; 1461: 237–62.
18. Litviakov NV, Cherdyntseva NV, Tsyganov MM, et al. Changing the expression vector of multidrug resistance genes is related to neoadjuvant chemotherapy response. Cancer Chemother Pharmacol 2013; 71: 153–163.
19. Tamaki A, Ierano C, Szakacs G, et al. The controversial role of ABC transporters in clinical oncology. Essays Biochem 2011; 50: 209–32.
20. Jones PM, O’Mara ML, George AM. ABC transpor­ters: a riddle wrapped in a mystery inside an enigma. Trends Biochem Sci 2009; 34: 520–31.
21. Walker JE, Saraste M, Runswick MJ, et al. Distantly related sequences in the alpha- and beta-subunits of ATP synthase, myosin, kinases and other ATP-requiring enzymes and a common nucleotide binding fold. EMBO J 1982; 1: 945–51.
22. Sarkadi B, Homolya L, Szakács G, et al. Human multidrug resistance ABCB and ABCG transporters: participation in a chemoimmunity defense system. Physiol Rev 2006; 86: 1179–236.
23. Tusnády GE, Sarkadi B, Simon I, et al. Membrane topology of human ABC proteins. FEBBS Lett 2006; 580: 1017–22.
24. Rocchi E, Khodjakov A, Volk EL. The product of the ABC half-transporter gene ABCG2 (BCRP/MXR/ABCP) is expressed in the plasma membrane. Biochem Biophys Res Commun 2000; 271: 42–6.
25. Gutmann DA, Ward A, Urbatsch IL, et al. Under­standing polyspecificity of multidrug ABC transporters: closing in the gaps in ABCB1. Trends Biochem Sci 2010; 35: 36–42.
26. Neyfakh AA. Use of fluorescent dyes as molecular probes for the study of multidrug resistance. Exp Cell Res 1988; 174: 168–76.
27. Vulevic B, Chen Z, Boyd JT, et al. Cloning and cha­racterization of human adenosine 5-triphosphate-binding cassette, sub-family A, transporter 2 (ABCA2). Cancer Res 2001; 61: 3339–47.
28. Speicher LA, Sheridan VR, Godwin AK, et al. Resistance to the antimitotic drug estramustine is distinct from the multidrug resistant phenotype. Br J Cancer 1991; 64: 267–73.
29. Maciejczyk A, Jagoda E, Wysocka T, et al. ABCC2 (MRP2, cMOAT) localized in the nuclear envelope of breast carcinoma cells correlates with poor clinical outcome. Pathol Oncol Res 2012; 18: 331–42.
30. Chang XB. A molecular understanding of ATP-dependent solute transport by multidrug resistance-associated protein MRP1. Cancer Metastasis Rev 2007; 26: 15–37.
31. König J, Nies AT, Cui Y, et al. Conjugate export pumps of the multidrug resistance protein (MRP) family: localization, substrate specificity, and MRP2-mediated drug resistance. Biochim Biophys Acta 1999; 1461: 377–94.
32. Fojo AT, Ueda K, Slamon DJ, et al. Expression of a multidrug-resistance gene in human tumors and tissues. Proc Natl Acad Sci USA 1987; 84: 265–9.
33. Borst P, Evers R, Koo M, et al. Family of drug transporters: the multidrug resistance-associated proteins. J Natl Cancer Inst 2000; 92: 1295–300.
34. Hipfner DR, Deeley RG, Cole SP. Structural, mechanistic and clinical aspects of MRP1. Biochim Biophys Acta 1999; 1461: 359–76.
35. List AF. Role of multidrug resistance and its pharmacological modulation in acute myeloid leukemia. Leukemia 1996; 10: 937–42.
36. Loe DW, Deeley RG, Cole SPC. Biology of the multidrug resistance-associated protein, MRP. Eur J Cancer 1996; 32A: 945–57.
37. Moulder S. Intrinsic resistance to chemotherapy in breast cancer. Womens Health (Lond Engl) 2010; 6: 821–30.
38. Li WJ, Zhong SL, Wu YJ, et al. Systematic expression analysis of genes related to multidrug-resistance in isogenic docetaxel- and adriamycin-resistant breast cancer cell lines. Mol Biol Rep 2013; 40: 6143–50.
39. Flens MJ, Zaman GJ, van der Valk P, et al. Tissue distribution of the multidrug resistance protein. Am J Pathol 1996; 148: 1237–47.
40. Falasca M, Linton KJ. Investigational ABC transporter inhibitors. Expert Opin Invest Drugs 2012; 21: 657–66.
41. He M, Wei MJ. Reversing multidrug resistance by tyrosine kinase inhibitors. Chin J Cancer 2012; 31: 126–33.
42. Juliano RL, Ling V. A surface modulating drug permeability in Chinese hamster ovary cell mutants. Biochim Biophys Asta 1976; 455: 152–62.
43. Lipskaya LA, Grinchuk TM, Efimova EV, et al. Amplification and overexpression of the MDR family genes in СНО-К1 Chinese hamster cells that are resistant to ethydium bromide as well as in hybrids of sensitive and resistant cells. Cytology 1994; 36: 1236–44.
44. Grinchuk TM, Lipskaya LA, Artsybasheva IV, et al. Variability of the karyotype of CHLV-79 RJK Chinese hamster cells, characterized by multi-drug resistance, which is determined by amplification of the MDR family genes. Cytology 1996; 38: 161–71.
45. Nevzglyadova OV, Shvartsman PYa. P-glycoprotein-mediated multi-drug resistance of eukaryotic cells. Mol Bio­logy 1992; 26: 487–99.
46. Ueda K, Pastan I, Gottesman MM. Isolation and sequence of the promoter region of the human multidrug-resistance (P-glycoprotein) gene. J Biol Chem 1987; 262: 17432–6.
47. Chaudhary PM, Roninson IB. Induction of multidrug resistance in human cells trancient exposure to different chemotherapeutic drugs. J Natl Cancer Inst 1993; 85: 632–9.
48. Chin KV, Ueda K, Pastan I, et al. Modulation of activity of the promoter of the human MDR1 gene by Ras and TP53. Science 1992; 255: 459–62.
49. Bhushan A, Abramson R, Chiu JF, et al. Expression of c-fos in human and murine multidrug-resistant cells. Mol Pharmacol 1992; 42: 69–74.
50. Chaudhary PM, Roninsin IB. Expression and activity of P-glycoprotein a multidrug efflux pump, in human hematopoietic stem cells. Oncol Res 1992; 4: 281–90.
51. Erokhina MA, Stavrovskaya AA, Onitschenko GE. Reorganization of the elements of the cytoskeleton and the vacuolar system in tumor cells at early stages of multi-drug resistance development. Cytology 1997; 39: 1038–45.
52. Hutson JR, Koren G, Matthews SG. Placental ­P-glycoprotein and breast cancer resistance protein: influence of polymorphisms on fetal drug exposure and physiology. Placenta 2010; 31: 351–7.
53. Schinkel AH. The physiological function of drug-transporting P-glycoproteins. Semin Cancer Biol 1997; 8: 161–70.
54. Rao VV, Dahlheimer JL, Bardgett ME, et al. Choroid plexus epithelial expression of MDR1 P-glycoprotein and multidrug resistance-associated protein contribute to the blood-cerebrospinal-fluid drug-permeability barrier. Proc Natl Acad Sci USA 1999; 96: 3900–5.
55. Sekine I, Shimizu C, Nishio K, et al. A literature review of molecular markers predictive of clinical response to cytotoxic chemotherapy in patients with breast cancer. Int J Clin Oncol 2009; 14: 112–9.
56. Chen KG, Sikic BI. Molecular pathways: regulation and therapeutic implications of multidrug resistance. Clin Cancer Res 2012; 18: 1863–9.
57. Goldstein LJ. MDR1 gene expression in solid tumours. Eur J Cancer 1996; 32A: 1039–50.
58. Litviakov NV, Garbukov EYu, Slonimskaya EM, et al. Connection of metastasis-free survival in breast cancer patients and an expression vector of multidrug resistance genes in tumor during neoadjuvant chemotherapy. Vopr Onkologii 2013; 59: 334–40 (in Russian).
59. Shukla S, Ohnuma S, Ambudkar SV. Improving cancer chemotherapy with modulators of ABC drug transporters. Curr Drug Targets 2011; 12: 621–30.
60. Sandor V, Fojo T, Bates SE. Future perspectives for the development of P-glycoprotein modulators. Drug Resist Update 1998; 1: 190–200.
61. Sui H, Fan ZZ, Li Q. Signal transduction pathways and transcriptional mechanisms of ABCB1/Pgp-mediated multiple drug resistance in human cancer cell. J Int Med Res 2012; 40: 426–35.
62. Aguilar-Bryan L, Nichols CG, Wechsler SW, et al. Cloning of the beta cell high-affinity sulfonylurea receptor: a regulator of insulin secretion. Science 1995; 268: 423–6.
63. Norman M, Moldovan S, Seghers V, et al. Sulfonylurea receptor knockout causes glucose intolerance in mice that is not alleviated by concomitant somatostatin subtype receptor 5 knockout. Ann Surg 2002; 235: 767–74.
64. Toyoda Y, Hagiya Y, Adachi T, et al. MRP class of human ATP binding cassette (ABC) transporters: historical background and new research directions. Xenobiotica 2008; 38: 833–62.
65. Bakos E, Evers R, Szakács G, et al. Functional multidrug resistance protein (MRP) lacking the N-terminal transmembrane domain. J Biol Chem 1998; 273: 32167–75.
66. Ishikawa T. The ATP-dependent glutathione ­S-conjugate export pump. Trends Biochem Sci 1992; 17: 463–8.
67. Hipfner DR, Almquist KC, Leslie EM, et al. Membrane topology of the multidrug resistance protein (MRP). A study of glycosylation-site mutants reveals an extracytosolic NH2 terminus. J Biol Chem 1997; 272: 23623–30.
68. Yin J, Zhang J. Multidrug resistance-associated protein 1 (MRP1/ABCC1) polymorphism: from discovery to clinical application. J Central South Univ 2011; 36: 927–38.
69. Nooter K, Westerman AM, Flens MJ, et al. Expression of the multidrug resistance-associated protein (MRP) gene in human cancers. Clin Cancer Res 1995; 1: 1301–10.
70. Kruh GD, Gaughan KT, Godwin A, et al. Expression pattern of MRP in human tissues and adult solid tumor cell lines. J Natl Cancer Inst 1995; 87: 1256–8.
71. Huh HJ, Park CJ, Jang S, et al. Prognostic significance of multidrug resistance gene 1 (MDR1), multidrug resistance-related protein (MRP) and lung resistance protein (LRP) mRNA expression in acute leukemia. J Korean Med Sci 2006; 21: 253–8.
72. Cole SP, Sparks KE, Fraser K, et al. Pharmacological characterization of multidrug resistant MRP-transfected human tumor cells. Cancer Res 1994; 54: 5902–10.
73. Hooijberg JH, Broxterman HJ, Kool M, et al. Antifolate resistance mediated by the multidrug resistance proteins MRP1 and MRP2. Cancer Res 1999; 59: 2532–5.
74. Loe DW, Almquist KC, Deeley RG, et al. Multidrug resistance protein (MRP)-mediated transport of leukotriene C4 and chemotherapeutic agents in membrane vesicles. De­monstration of glutathione-dependent vincristine transport. J Biol Chem 1996; 271: 9675–82.
75. Holló Z, Homolya L, Hegedüs T, Sarkadi B. Transport properties of the multidrug resistance-associated protein (MRP) in human tumour cells. FEBBS Lett 1996; 383: 99–104.
76. Keppler D, Kartenbeck J. The canalicular conjugate export pump encoded by the cmrp/cmoat gene. Prog Liver Dis 1996; 14: 55–67.
77. Paulusma CC, Kool M, Bosma PJ, et al. A mutation in the human canalicular multispecific organic anion transporter gene causes the Dubin — Johnson syndrome. Hepato­logy 1997; 25: 1539–42.
78. Cui Y, König J, Buchholz JK, et al. Drug resistance and ATP-dependent conjugate transport mediated by the apical multidrug resistance protein, MRP2, permanently expressed in human and canine cells. Mol Pharmacol 1999; 55: 929–37.
79. Kool M, de Haas M, Scheffer GL, et al. Analysis of expression of cMOAT (MRP2), MRP3, MRP4, and MRP5, homologues of the multidrug resistance-associated protein gene (MRP1), in human cancer cell lines. Cancer Res 1997; 57: 3537–47.
80. Hirohashi T, Suzuki H, Sugiyama Y. Characterization of the transport properties of cloned rat multidrug resistance-associated protein 3 (MRP3). J Biol Chem 1999; 274: 15181–5.
81. Young LC, Campling BG, Voskoglou-Nomikos T, et al. Expression of multidrug resistance protein-related genes in lung cancer: correlation with drug response. Clin Cancer Res 1999; 5: 673–80.
82. Kool M, van der Linden M, de Haas M, et al. MRP3, an organic anion transporter able to transport anti-cancer drugs. Proc Natl Acad Sci USA 1999; 96: 6914–9.
83. Schuetz JD, Connelly MC, Sun D, et al. MRP4: a previously unidentified factor in resistance to nucleoside-based antiviral drugs. Nat Med 1999; 5: 1048–51.
84. Lee K, Klein-Szanto AJ, Kruh GD. Analysis of the MRP4 drug resistance profile in transfected ­NIH3T3 cells. J Natl Cancer Inst 2000; 92: 1934–40.
85. Lai L, Tan TM. Role of glutathione in the multidrug resistance protein 4 (MRP4/ABCC4)-mediated efflux of cAMP and resistance to purine analogues. Biochem J 2002; 361: 497–503.
86. McAleer MA, Breen MA, White NL, et al. pABC11 (also known as MOAT-C and MRP5), a member of the ABC family of proteins, has anion transporter activity but does not confer multidrug resistance when overexpressed in human embryonic kidney 293 cells. J Biol Chem 1999; 274: 23541–8.
87. Wijnholds J, Mol CA, van Deemter L, et al. Multidrug-resistance protein 5 is a multispecific organic anion transporter able to transport nucleotide analogs. Proc Natl Acad Sci USA 2000; 97: 7476–81.
88. Bergen AA, Plomp AS, Schuurman EJ, et al. Mutations in ABCC6 cause pseudoxanthoma elasticum. Nat Genet 2000; 25: 228–31.
89. Belinsky MG, Chen ZS, Shchaveleva I, et al. Drug-resistance phenotype of multidrug-resistance protein-6-transfected Chinese hamster ovary cells. Proc Am Assoc Cancer Res 2001; 42: 281.
90. Kool M, van der Linden M, de Haas M, et al. Expression of human MRP6, a homologue of the multidrug resistance protein gene MRP1, in tissues and cancer cells. Cancer Res 1999; 59: 175–82.
91. O’Neill GM, Peters GB, Harvie RM, et al. Amplification and expression of the ABC transporters ARA and MRP in a series of multidrug-resistant leukaemia cell sublines. Br J Cancer 1998; 77: 2076–80.
92. Hopper E, Belinsky MG, Zeng H, et al. Analysis of the structure and expression pattern of MRP7 (ABCC10), a new member of the MRP subfamily. Cancer Lett 2001; 162: 181–91.
93. Tammur J, Prades C, Arnould I, et al. Two new genes from the human ATP-binding cassette transporter superfamily, ABCC11 and ABCC12, tandemly duplicated on chromosome 16q12. Gene (Amst) 2001; 273: 89–96.
94. Bera TK, Lee S, Salvatore G, et al. MRP8, a new member of ABC transporter superfamily, identified by EST database mining and gene prediction program, is highly expressed in breast cancer. Mol Med 2001; 7: 509–16.
95. Bera TK, Iavarone C, Kumar V, et al. MRP9, an ­unusual truncated member of the ABC transporter superfamily, is highly expressed in breast cancer. Proc Natl Acad Sci USA 2002; 99: 6997–7002.
96. Kerr ID, Haider AJ, Gelissen IC. The ABCG family of membrane-associated transporters: you don’t have to be big to be mighty. Br J Parmacol 2011; 164: 1767–79.
97. Berge KE, Tian H, Graf GA, et al. Accumulation of dietary cholesterol in sitosterolemia caused by mutations in adjacent ABC transporters. Science 2000; 290: 1771–5.
98. Matsuo M. ATP-binding cassette proteins involved in glucose and lipid homeostasis. Biosci Biotechnol Biochem 2010; 74: 899–907.
99. Hirayama H, Kimura Y, Kioka N, et al. ATPase activity of human ABCG1 is stimulated by cholesterol and sphingomyelin. J Lipid Res 2013; 54: 496–502.
100. Tarling EJ. Expanding roles of ABCG1 and sterol transport. Curr Opin Lipidol 2013; 24: 138–46.
101. von Eckardstein A, Sibler RA. Possible contributions of lipoproteins and cholesterol to the pathogenesis of diabetes mellitus type 2. Curr Opin Lipidol 2011; 22: 26–32.
102. Schou J, Tybjærg-Hansen A, Møller HJ, et al. ABC transporter genes and risk of type 2 diabetes: a study of 40.000 individuals from the general population. Diabetes Care 2012; 35: 2600–6.
103. Westerterp M, Bochem AE, Yvan-Charvet L, et al. ATP-binding cassette transporters, atherosclerosis, and inflammation. Circ Res 2014; 114: 157–70.
104. Ye D, Lammers B, Zhao Y, et al. ATP-binding cassette transporters A1 and G1, HDL metabolism, cholesterol efflux, and inflammation: important targets for the treatment of atherosclerosis. Curr Drug Targets 2011; 12: 647–60.
105. Hlavač V, Brynychova V, Vaclavikova R, et al. The expression profile of ATP-binding cassette transporter genes in breast carcinoma. Pharmacogenomics 2013; 14: 515–29.
106. Robey RW, To KK, Polgar O, et al. ABCG2: a perspective. Adv Drug Deliv Rev 2009; 6: 3–13.
107. Ganghi YA, Morris ME. Structure-activity relationships and quantitative structure-activity relationships for breast cancer resistanceprotein (ABCG2). AAPS J 2009; 11: 541–52.
108. Natarajan K, Xie Y, Baer MR, et al. Role of breast cancer resistance protein (BCRP/ABCG2) in cancer drug resistance. Biochem Pharmacol 2012; 83: 1084–103.
109. Ni Z, Bikadi Z, Rosenberg MF, et al. Structure and function of the human breast cancer resistance protein (BCRP/ABCG2). Curr Drug Metab 2010; 11: 603–17.
110. Marighetti F, Steggemann K, Hanl M, et al. Synthesis and quantitative structure-activity relationships of selective BCRP inhibitors. Chem Med Chem 2013; 8: 125–35.
111. Scheffer GL, Maliepaard M, Pijnenborg AC, et al. Breast cancer resistance protein is localized at the plasma membrane in mitoxantrone- and topotecan-resistant cell lines. Cancer Res 2000; 60: 2589–93.
112. Koshiba S, An R, Saito H, et al. Human ABC transporters ABCG2 (BCRP) and ABCG4. Xenobiotica 2008; 38: 863–88.
113. Doyle LA, Ross DD. Multidrug resistance mediated by the breast cancer resistance protein BCRP (ABCG2). Oncogene 2003; 22: 7340–58.
114. Krishnamurthy P, Xie T, Schuetz JD. The role of transporters in cellular heme and porphyrin homeostasis. Pharmacol Ther 2007; 114: 345–58.
115. van Herwaarden AE, Wagenaar E, Merino G, et al. Multidrug transporter ABCG2/breast cancer resistance protein secretes riboflavin (vitamin B2) into milk. Mol Cell Biol 2007; 27: 1247–53.
116. Grube M, Reuther S, Meyer Zu Schwabedissen H, et al. Organic anion transporting polypeptide 2B1 and breast cancer resistance protein interact in the transepithelial transport of steroid sulfates in human placenta. Drug Metab Dispos 2007; 35: 30–5.
117. Cooray HC, Blackmore CG, Maskell L. Localisation of breast cancer resistance protein in microvessel endotheliumof human brain. Neuroreport 2002; 13: 2059–63.
118. Selever J, Gu G, Lewis MT, et al. Dicer-mediated upregulation of BCRP confers tamoxifen resistance in human breast cancer cells. Clin Cancer Res 2011; 17: 6510–21.
119. Kawabata S, Oka M, Soda H, et al. Expression and functional analyses of breast cancer resistance protein in lung cancer. Clin Cancer Res 2003; 9: 3052–7.
120. Wu AM, Dalvi P, Lu X, et al. Induction of multidrug resistance transporter ABCG2 by prolactin in human breast cancer cells. Mol Pharmacol 2013; 83: 377–88.
121. Steinbach D, Sell W, Voigt A, et al. BCRP gene expression is associated with a poor response to remission induction therapy in childhood acute myeloid leukemia. Leukemia (Baltimore) 2002; 16: 1443–7.
122. Ross DD, Karp JE, Chen TT, et al. Expression of breast cancer resistance protein in blast cells from patients with acute leukemia. Blood 2000; 96: 365–8.
123. Doyle LA, Yang W, Abruzzo LV, et al. A multidrug resistance transporter from human MCF-7 breast cancer cells. Proc Natl Acad Sci USA 1998; 95: 15665–70.
124. An Y, Ongkeko WM. ABCG2: the key to chemoresistance in cancer stem cells? Expert Opin Drug Metabol Toxicol 2009; 5: 1529–42.
125. Liu F, Fan D, Qi J, et al. Co-expression of cytokeratin 8 and breast cancer resistant protein indicates a multifactorial drug-resistant phenotype in human breast cancer cell line. Life Sci 2008; 83: 496–501.
126. Noguchi K, Katayama K, Mitsuhashi J, et al. Functions of the breast cancer resistance protein (BCRP/ABCG2) in chemotherapy. Adv Drug Deliv Rev 2009; 61: 26–33.
127. Board PG, Menon D. Glutathione transferases, regulators of cellular metabolism and physiology. Biochim Biophys Acta 2013; 1830: 3297–88.
128. Tew KD, Townsend DM. Regulatory functions of glutathione S-transferase P1–1 unrelated to detoxification. Drug Metabol Rev 2011; 43: 179–93.
129. Kulinsky VI. Detoxification of xenobiotics. Soros Educat J 1999; 1: 8–12.
130. Gul O, Basaga H, Kutuk O. Apoptotic blocks and chemotherapy resistance: strategies to identify Bcl-2protein signatures. Brief Funct Genomic Proteomic 2008; 7: 27–34.
131. Laborde E. Glutathione transferases as mediators of signaling pathways involved in cell proliferation and cell death. Cell Death Differ 2010; 17: 1373–80.
132. Lavigne JA, Helzlsouer KJ, Huang HY, et al. An association between the allele coding for a low activity variant of catechol-O-methyltransferase and the risk for breast cancer. Cancer Res 1997; 57: 5493–7.
133. Cao K, Stack DE, Ramanathan R, et al. Synthesis and structure elucidation of estrogen quinones conjugated with cysteine, N-acetylcysteine, and glutathione. Chem Res Toxicol 1998; 11: 908–16.
134. Zhu ВТ, Conney AH. Functional role of estrogen metabolism in target cells: review and perspectives. Carcinogenesis 1998; 19: 1–27.
135. Helzlsouer KJ, Huang HY, Strickland PT, et al. Association between CYP17 polymorphisms and the development of breast cancer. Cancer Epidemiol Biomarkers Prev 1998; 7: 945–50.
136. Di Pietro G, Magno LA, Rios-Santos F. Glutathione S-transferases: an overview in cancer research. Expert Opin Drug Metabol Toxicol 2010; 6: 153–70.
137. Wang J, Xiao Z. RQ-PCR detection of GST-π and LRP genes in adult acute leukemia and its clinical significance. Zhongguo Shi Yan Xue Ye Xue Za Zhi 2012; 20: 78–82.
138. Ekhart C, Rodenhuis S, Smits PH, et al. An overview of the relations between polymorphisms in drug metabolising enzymes and drug transporters and survival after cancer drug treatment. Cancer Treat Rev 2009; 35: 18–31.
139. Dederer LYu, Lankin VZ, Konovalova AL, et al. Studying of the biochemical mechanisms of resistance to a new anti-tumor drug amine(cyclopentilamine)-S-(-)-malate platinum (II) (cycloplatam). Biochemistry 1995; 60: 602–9.
140. Backos DS, Franklin CC, Reigan P. The role of glutathione in brain tumor drug resistance. Biochem Pharmacol 2012; 83: 1005–12.
141. Morrow CS, Smitherman PK, Townsend AJ. Role of multidrug-resistance protein 2 in glutathione S-transferase P1–1-mediated resistance to 4-nitroquinoline 1-oxide toxi­cities in HepG2 cells. Mol Carcinogenesis 2000; 29: 170–8.
142. Morrow CS, Diah S, Smitherman PK, et al. Multidrug resistance protein and glutathione S-transferase P1–1 act in synergy to confer protection from 4-nitroquinoline 1-oxide toxicity. Carcinogenesis 1998; 19: 109–15.
143. Sau A, Pellizzari Tregno F, Valentino F, et al. Glutathione transferases and development of new principles to overcome drug resistance. Arch Biochem Biophys 2010; 500: 116–22.
144. Ruzza P, Rosato A, Rossi CR, et al. Glutathione transferases as targets for cancer therapy. Anticancer Agents Med Chem 2009; 9: 763–77.
145. McCurrach ME, Connor TM, Knudson CM, et al. Bax-deficiency promotes drug resistance and oncogenic transformation by attenuating p53-dependent apoptosis. Proc Natl Sci USA 1996; 94: 2345–9.
146. Gerl R, Vaux DL. Apoptosis in the development and treatment of cancer. Carcinogenesis 2005; 26: 263–324.
147. Giménez-Bonafé P, Tortosa A, Pérez-Tomás R. Overcoming drug resistance by enhancing apoptosis of tumor cells. Curr Cancer Drug Targets 2009; 9: 320–40.
148. Saeidnia S, Abdollahi M. Antioxidants: friends or foe in prevention or treatment of cancer: the debate of the century. Toxicol Appl Pharmacol 2013; 271: 49–63.
149. Kim R, Emi M, Tanabe K, et al. The role of apoptotic or nonapoptotic cell death in determining cellular response to anticancer treatment. Eur J Surg Oncol 2006; 32: 269–77.
150. Kopnin BP. Targets of the effects of oncogenes and tumor suppressors: the key to understanding of the foundations of carcinogenesis mechanisms. Biochemistry 2000; 65: 5–33.
151. Chumakov PM. The function of the p53 gene: the choice between life and death. Biochemistry 2000; 65: 34–47.
152. Meulmeester E, Jochemsen AG. p53: a guide to apoptosis. Curr Cancer Drug Targets 2008; 8: 87–97.
153. Fuster JJ, Sanz-Gonzalez SM, Moll UM, et al. Classic and novel roles of p53: prospects for anticancer therapy. Trends Mol Med 2007; 13: 192–9.
154. Kastan MB. Wild-type p53: tumors can’t stand it. Cell 2007; 128: 837–40.
155. Fulda S. Regulation of apoptosis pathways in cancer stem cells. Cancer Lett 2013; 338: 168–73.
156. Martinez-Rivera M, Siddik ZH. Resistance and gain-of-resistance phenotypes in cancers harboring wild-type p53. Biochem Pharmacol 2007; 83: 1049–62.
157. Saha MN, Micallef J, Qiu L, et al. Pharmacological activation of the p53 pathway in haematological malignancies. J Clin Pathol 2010; 63: 204–9.
158. Brosh R, Rotter V. When mutants gain new powers: news from the mutant p53 field. Nat Rev Cancer 2009; 9: 701–13.
159. Bar J, Moskovits N, Oren M. Involvement of stromal p53 in tumor-stroma interactions. Semin Cell Dev Biol 2010; 21: 47–54.
160. Conklin MW, Keely PJ. Why the stroma matters in breast cancer: insights into breast cancer patient outcomes through the examination of stromal biomarkers. Cell Adh Migr 2012; 6: 249–60.
161. Glaccia AJ, Kastan MB. The complexity of p53 modulation: emerging patterns from divergent. Genes Dev 1998; 12: 2973–83.
162. Van Brussel JP, Jan Van Steenbrugge G, Van Krimpen C, et al. Expression of multidrug resistance related proteins and proliferative activity is increased in advanced clinical prostate cancer. J Urol 2001; 165: 130–5.
163. Sullivan GF, Yang JM, Vassil A, et al. Regulation of expression of the multidrug resistance protein MRP1 by p53 in human prostate cancer cells. J Clin Invest 2000; 105: 1261–7.
164. Mashima T, Tsuruo T. Defects of the apoptotic pathway as therapeutic target against cancer. Drug Resist Updat 2005; 8: 339–43.
165. Prabhu VV, Allen JE, Hong B, et al. Therapeutic targeting of the p53 pathway in cancer stem cells. Expert Opin Ther Targets 2012; 16: 1161–74.
166. Kirkin V, Joos S, Zörnig M. The role of Bcl-2 fami­ly members in tumorigenesis. Biochim Biophys Acta 2004; 1644: 229–49.
167. Adams JM, Cory S. The Bcl-2 protein family: arbiters of cell survival. Science 1998; 281: 1322–6.
168. Krajewska M, Moss SF, Krajewski S, et al. Elevated expression of Bcl-x and reduced Bak expression in primary rectal adenocarcinomas. Cancer Res 1996; 56: 2422–32.
169. Dive C. Avoidance of apoptosis as a mechanism of drug resistance. J Intern Med 1997; 242: 139–45.
170. Allouche M, Bettaieb A, Vindis C, et al. Influence of the Bcl-2 overexpression on the ceramide pathway in daunorubicin-induced apoptosis of leukemic cells. Oncogene 1997; 14: 1837–45.
171. Laroche-Clary A, Larrue A, Robert J. Down-regulation of bcr-abl and bcl-x(L) expression in a leukemia cell line and its doxorubicin-resistant variant by topoisomerase II inhibitors. Biochem Pharmacol 2000; 60: 1823–8.
172. Azad N, Iyer A, Vallyathan V, et al. Role of oxidative/nitrosative stress-mediated Bcl-2 regulation in apoptosis and malignant transformation. Ann N Y Acad Sci USA 2010; 1203: 1–6.
173. Tewari M, Krishnamurthy A, Shukla HS. Predictive markers of response to neoadjuvant chemotherapy in breast cancer. Surg Oncol 2008; 17: 301–11.
174. Zhu CQ, Shih W, Ling CH, et al. Immunohistochemical markers of prognosis in non-small cell lung cancer: a review and proposal for a multiphase approach to marker evaluation. J Clin Pathol 2006; 59: 790–800.
175. Callagy GM, Webber MJ, Pharoah PD, et al. Meta-analysis confirms BCL2 is an independent prognostic marker in breast cancer. BMC Cancer 2008; 8: 153.
176. Minn A, Rudin CM, Boise LH. Expression of Bcl-xL can confer multidrug resistant phenotype. Blood 1995; 86: 1903–07.
177. Cakir E, Yilmaz A, Demirag F, et al. Prognostic significance of micropapillary pattern in lung adenocarcinoma and expression of apoptosis-related markers: caspase-3, bcl-2, and p53. APMIS 2011; 119: 574–80.
178. Sumantran VN, Ealovega MW, Nuñez G, et al. Overexpression of Bcl-XS sensitizes MCF-7 cells to chemotherapy-induced apoptosis. Cancer Res 1995; 55: 2507–10.
179. Frassoldati A, Maur M, Guarneri V, et al. Predictive value of biologic parameters for primary chemotherapy in operable breast cancer. Clin Breast Cancer 2005; 6: 315–24.
180. Thomadaki H, Scorilas A. Molecular profile of the BCL2 family of the apoptosis related genes in breast cancer cells after treatment with cytotoxic/cytostatic drugs. Connect Tissue Res 2008; 49: 261–4.
181. Richardson A, Kaye SB. Pharmacological inhibition of the Bcl-2 family of apoptosis regulators as cancer therapy. Curr Mol Pharmacol 2008; 1: 244–54.
182. Weyhenmeyer B, Murphy AC, Prehn JH, et al. ­Targeting the anti-apoptotic Bcl-2 family members for the treatment of cancer. Exp Oncol 2012; 34: 192–9.
183. Thomas S, Quinn BA, Das SK, et al. Targeting the Bcl-2 family for cancer therapy. Expert Opin Ther Targets 2013; 17: 61–75.
184. Stauffer SR. Small molecule inhibition of the Bcl-X(L)-BH3 protein-protein interaction: proof-of-concept of an in vivo chemopotentiator ABT-737. Curr Top. Med Chem 2007; 7: 961–5.
185. Vogler M, Dinsdale D, Dyer MJ, et al. Bcl-2 inhibitors: small molecules with a big impact on cancer therapy. Cell Death Differ 2009; 16: 360–7.
186. Buggins AG, Pepper CJ. The role of Bcl-2 family proteins in chronic lymphocytic leukaemia. Leuk Res 2010; 34: 837–42.
187. Hickman JA, Potten CS, Merritt AJ, et al. Apoptosis and cancer chemotherapy. Phil Trans R Soc 1994; 345: 319–25.
188. Miyashita T, Reed JC. Bcl-2 oncoprotein blocks chemotherapy induced apoptosis in a human leukemia cell line. Blood 1993; 81: 151–7.
189. Blagosklonny MV, Giannakakou P, el-Deiry WS, et al. Raf-1/bcl-2 phosphorylation: a step from microtubule damage to cell death. Cancer Res 1997; 57: 130–5.
190. Osbild S, Brault L, Battaglia E, et al. Resistance to cisplatin and adriamycin is associated with the inhibition of glutathione efflux in MCF-7-derived cells. Anticancer Res 2006; 26: 3595–600.
191. Scata KA, El-Deiry WS. p53, BRCA1 and breast cancer chemoresistance. Adv Exp Med Biol 2007; 608: 70–86.

No Comments » Add comments
Leave a comment

ERROR: si-captcha.php plugin says GD image support not detected in PHP!

Contact your web host and ask them why GD image support is not enabled for PHP.

ERROR: si-captcha.php plugin says imagepng function not detected in PHP!

Contact your web host and ask them why imagepng function is not enabled for PHP.