ABC transporters in anticancer drug transport
Transcription
ABC transporters in anticancer drug transport
Copyright © 2015 By IYPF All rights reserved Open Access Contents Int. J. Drug Dev. & Res. | January - March 2015 | Vol. 7 | Issue 1 | ISSN 0975-9344 | www.ijddr.in ABC transporters in anticancer drug transport – Lessons for Therapy, Drug Development and Delivery Systems Suresh P.K. 1 Abstract: The structural aspects as well as the classification of the ABC superfamily (the largest group Vembuli Amman Varadharaj.*2 of transmembrane proteins) has been highlighted. Over-expression of one or more of these 1Prof., SBST, VIT University, Vellore, Vellore Dt. PIN: 632014. 2Research Scholar, SBST, VIT University, Vellore, Vellore Dt. PIN: 632014 Corresponding Authors: Email: [email protected] Mobile: 9444047684 Keywords: ABC transporter; P-gP glycoprotein; drug efflux; drug uptake; SLC; MDR phenotype; polypharmacy; combination therapy; cancer stem cells; nanoparticle /nanotechnology. Page 127 Walker B motif separated by about 90-120 amino I 1. ntroduction to ATP – binding cassette (ABC) acids, along with a distinctive C-motif upstream of transporters and P-glycoprotein (P-gP) ABC transporters of transmembrane domains (typically 12, however, 2012; the number of helices can vary) and the NBFs Karwar, 2014), which utilize the energy from ATP (localized in the cytoplasm and involved in energy hydrolysis to translocate many molecules across transfer for substrate transport). Heterogeneity in biological membranes. This translocation may be the TM domains has been reported and they have from within the cell to the endoplasmic reticulum; been reclassified as Type I importer; Type II mitochondria or to the exterior of the cell. In the importer and ABC exporter (Locher, 2008). These latter unidirectional transporters can have 1 TM and 1 NBF (half- pump may be necessary for the transport to other transporter) or can be a full transporter (2 TMs and organs or excretion from the body. Further, the 2 NBFs). In the former case, they can homo or membrane hetero-dimerize to produce a fully functional transmembrane case, are the proteins the largest the Walker B site. This protein has two each of the (Scott predominantly protein has certain et family al., non-transport functions, as in translation and DNA repair transporter (Davidson et al., 2008; Goffeau et al., 2004). They transporters are involved in ferrying endogenous have acquired this name, since they have a compounds like metabolic products, lipids, sterols characteristic across ATP-binding domain (NBF- the (Borst and cellular Elferink membranes, 2002). apart These from nucleotide binding fold). This domain (found in all exogenous drugs including those for treating ATP-binding proteins) consists of a Walker A and a cancer (Deeley et al., 2006). Covered in Scopus & Embase, Elsevier Int. J. Drug Dev. & Res., January-March 2015, 7 (1): 127-136 © 2015 Suresh P.K. et al, publisher and licensee IYPF. This is an Open Access article which permits unrestricted noncommercial use, provided the original work is properly cited. Full Length Original Research Paper transporters, barring exceptions, can correlate with an increased drug resistance (the multidrug resistance phenotype). Hence, studying these proteins, using experimental and in silico approaches, has tremendous benefit for patient selection as well as stratification into “good” and “poor” drug responders. Further, the need to obtain a better insight into “intrinsic” and “extrinsic” mechanisms of resistance were reiterated upon, based on the relative recruitment of the different signal transduction molecules. The concept of the reversal of the MDR phenotype, has been discussed and extended in the context of combination therapy. This form of therapy involves the use of a cocktail of synthetic and biopharmaceutical drugs as well as nanotechnology-based approaches, for improvements in their pharmacokinetic (PK) and pharmacodynamic (PD) profile. Such strategies have targeted the heterogeneous cancer and cancer stem cells, signaling molecules, marker enzymes as well as the microenvironment for improved efficacy and safety as well as to minimize the chance of relapse. Jayasindu Mathiyazhagan.*2 binding (Chufan et al., 2015). However, results evolution) seven obtained were based on X-ray crystallography mammalian subfamilies (ABCA; ABCB; ABCC; data from mice. Currently, further research has ABCD; ABCE; ABCF; ABCG) based on the structure been of the gene (49 genes in humans); sequence crystallography homology in the TM and NBF domains; as well as necessitating computational approaches with the in the organization of the domains. ABCA1 homology-modeled human glycoprotein (Cleave subfamily further SS et al. 2013). It is hoped that such an approach classified into 2 groups. Seven proteins form part of may provide more insights into their possible 1 group, while the other group has five proteins. differential affinity of binding (anti-cancer drugs) The former category of proteins has their genes with the inward (closed conformation) and the dispersed in different chromosomes, while in the outward (open conformation) forms of the protein case of the latter; they are all clustered together and hence may provide a better understanding on – of drug resistance. While the ABCC subfamily has transporters P-glycoprotein (ABCB1) is one of the 12 transporters, the proteins relevant to drugs are most clinically relevant protein and was the first to ABCC1, ABCC2 and ABCC3. ABCC1 has a similar be characterized for its ability to confer an Multi “drug-efflux profile” when compared with that of Drug Resistance (MDR) phenotype in cancer cells. ABCB1. However, these proteins are involved Members of this subfamily are four full transporters mainly and mainly glutathione and other organic anions Four genes localized in the brain and in the liver (Dean et al., make up the ABCD subfamily in humans. They are 2001). This transporter is able to efflux structurally not directly involved in drug transport. They (half- diverse category of hydrophobic drugs (broad transporters) have been reported to be involved spectrum) adriamycin, in fatty acid transport and oxidation in the vinblastine and VP16. The intriguing and puzzling peroxisome. Both ABCE and ABCF subfamilies finding of cross-resistance to a multitude of have no TM region and hence are not involved in different (with anti-cancer drug transport, despite possessing notable exceptions being platinum compounds, ATP-binding domains. Members of the last family nucleoside analogs, or alkylating agents) was (ABCG) have six “reverse” half-transporters. These resolved, in major part, by the discovery of the proteins have a NBF at the amino terminus and a aforesaid flexible, 170 kDa P-glycoprotein (P-gP) in TM domain at the carboxyl terminus. Of all the the 1970s (Juliano and Ling, 1976; Juranka et al., genes in this family, drug resistance has been 1989). Corroborative evidence for the flexibility of attributed to ABCG2 (ABCP, MXR1, BCRP). Gene this protein has been demonstrated in mice and amplification or chromosomal translocation may humans chemical, be the major mechanisms responsible for the biochemical, biophysical, genetic and molecular observed resistance to chemotherapeutic drugs in modeling approaches. Further, the protein has the anthracycline family (Dean et al. 2001). Apart been shown to have a common drug-binding from the family of ABC transporters, there are pocket with partially overlapping sites for substrate some proteins that are related, at least in part, one have (12 been transporters) chromosome seven-half classes a of has into been (17q24). transporters including using classified The and are colchicine, anti-cancer combination ABC drugs of hampered in by data removing the on lack the drugs of X-ray human conjugated P-gP to Covered in Scopus & Embase, Elsevier Int. J. Drug Dev. & Res., January-March 2015, 7 (1): 280-285 © 2015 Suresh P.K. et al, publisher and licensee IYPF. This is an Open Access article which permits unrestricted noncommercial use, provided the original work is properly cited. Page 128 Suresh P.K. et al; ABC transporters in anticancer drug transport – Lessons for Therapy, Drug Development and Delivery Systems These transporters (highly conserved throughout structurally to this family. They belong to the Increased expression of P-gP has been correlated multidrug resistance associated protein family with (MRP) and consists of nine members (Kruh and reported for both solid tumors as well as for Belinsky 2003). This aspect (topic for another leukemias. For e.g., In a study involving 50 patients review) should also be seen from the oft repeated with paradigm, in terms of redundancy of toxicant NeoAdjuvant efflux mechanism (back-up) being used for the immuno-histochemical fortuitous removal of anti-cancer drugs. evidence for an inverse correlation between P-gP poor prognosis. locally This aspect advanced has breast ChemoTherapy been cancer, (NACT) findings and provided expression and drug response. In other words, the patients who were positive for P-gP expression Chemotherapy –Targeting Multi Drug before NACT, were poor responders (Singh et al., Page 129 resistance (MDR) in cancer 2005). Drug resistance is the prime cause of death in standardized, inexpensive screening test for the cancer and 30-80% of the cancer treatments fail detection of P-glycoprotein as well as multidrug due to resistance to cytotoxic drugs (Velingkar resistance-associated protein activities) indicated and Dandekar, 2010). The expression of ABC that there was a 69% chance of the therapy transporters increases with the exposure to a wide failing in patients with MDR positivity. Further, there spectrum of anti-cancer drugs which are synthetic was a 72% chance of a positive response in or natural in origin. These drugs fit into one among patients testing negative for the MDR phenotype the several classes and include mitotic spindle (Karászi et al., 2001). disruptors (vinca alkaloids -vinorelbine, vincristine, Increased Expression of P-gP has been correlated vinblastine); DNA intercalators that inhibit the with the increasing levels of acquired drug progression of topoisomerase II complexes as well resistance and the development of the MDR as generators phenotype. This form of resistance is known as daunorubicin; having been “acquired” and may be due to cytotoxic (anthracyclines epirubicin); free radical –doxorubicin; microtubule-disrupting diterpenes Calcein efflux assay (quantitative, copy number changes and/or increases in gene (taxanes -Paclitaxel, Docetaxel); cytotoxic topo-II expression inhibitors-epipodophyllotoxins laboratory-based experiments and clinical studies (etoposide, and has been demonstrated in teniposide); Topoisomerase I inhibitor (topotecan); (Grogan polypeptide antibiotics DNA reported a possible intercellular transfer of the P- transcription (dactinomycin); aziridine- gp as well as the “acquired resistant” MDR containing, natural DNA crosslinker-mitomycin C phenotype to the PgP negative cells (Levchenko and, barring exceptions (platinum compounds, et al., 2005). In other cases, the endogenously- nucleoside analogs as well as alkylating agents) high, intrinsic tissue-specific expression of P-gP (for are known to be effluxed by these transporters, e.g., epithelial cells of the colon, kidney, adrenal, and they have a broad substrate specificity. This is pancreas, and liver) accounts for the initially high the case, despite the differences in the respective efflux, mechanisms of action of the aforesaid different resistance types resistance is translated into a decrease in the of drugs. (Krishna which and inhibit and Mayer, 2000). et and al., 1993). hence to such Further, faster others have development anti-cancer drugs. of This Covered in Scopus & Embase, Elsevier Int. J. Drug Dev. & Res., January-March 2015, 7 (1): 127-136 © 2015 Suresh P.K. et al, publisher and licensee IYPF. This is an Open Access article which permits unrestricted noncommercial use, provided the original work is properly cited. Full Length Original Research Paper 2. and the dose-dependent micronization-based strategies of existing drugs; increase in toxicity (Fardel et al., 1996). Further, improvements in the physico-chemical properties intrinsic (hydrophobilicty resistance possible may be related to the vs hydrophilicity and acquisition of genetic mutations in the genes nanotechnology-based encoding for this transporter protein (Szakács et (combination therapy) methods (Liu et al., 2014). al., 2006). These findings have provided an This mode of therapy has also been demonstrated impetus for mechanistic studies to be performed model systems. For e.g., upregulation of proteins to document the differences as well as common including MDR1-mediated resistance to paclitaxel signal transduction pathways that can provide a has been reported in certain cell lines. As a better molecular profile of drug resistance. In this possible strategy to circumvent this problem, regard, for paclitaxel, NF-kB as well as pregnane X resveratrol (a flavanoid from a natural source) has receptor (PXR)-mediated pathways were involved been in P-gP-mediated drug resistance. In the case of (Sprouse and Herbert, 2014). Also, repurposing of doxorubicin, it has been reported that NF-κb existing drugs can also been done, especially pathway was primarily involved. Hence, different done after an improved understanding has been strategies may need to be adopted for P-gP- obtained of the factors contributing to the intrinsic mediated anti-cancer and extrinsic resistance to existing anti-cancer drugs (Xu et al., 2014) in the context of target drugs. For e.g., certain micro-RNAs have been identification/validation. several known to contribute to drug resistance in non- polymorphisms in the MDR1 gene have been small cell lung cancer. A better understanding of identified and can these pathways can provide a more-targeted contribute to efflux approach to resolving this age-old problem of capabilities. For e.g., a case-control study showed MDR (Tibaldi et al., 2015). The current research that the CC/TT genotype (1236 codon in exon efforts are also geared towards the development 12) in the MDR1 gene conferred the “poor of nano-particle-based approaches for inhibiting responder status”, in a Saudi Arabian population or circumventing these efflux mechanisms. Such of breast cancer patients, to the standard efforts would complement the existing strategies chemotherapeutic regimen (Alsaif et al., 2013). In of using compounds that are known to bypass P- certain cases, even synonymous changes can gP (Platinum compounds, nucleoside analogs alter the conformation and hence the substrate and alkylating agents) or to and inhibitor binding sites despite their being no versions of the existing drugs, such that they are change in the coding sequences (Kimchi-Sarfaty not et al., 2007). (Yoshikawa et al., 2004; Nobili et al., 2011). While resistance such to different Further, genetic alterations in variants the drug used in substrates based combination of this polypharmacy with paclitaxel develop modified transporter protein this topic has been reviewed by others, a brief 3. Strategies on the reversal of MDR in cancer summary here, especially in the context of drug efflux and the MDR phenotype would enable the Research is ongoing globally to decrease toxicity reader to obtain a comprehensive understanding and improve the efficacy of P-gP inhibitors of the current developments in the field. These (improved PK/PD profile). These efforts include include the development of polymers, lipids, Covered in Scopus & Embase, Elsevier Int. J. Drug Dev. & Res., January-March 2015, 7 (1): 127-136 © 2015 Suresh P.K. et al, publisher and licensee IYPF. This is an Open Access article which permits unrestricted noncommercial use, provided the original work is properly cited. Page 130 Suresh P.K. et al; ABC transporters in anticancer drug transport – Lessons for Therapy, Drug Development and Delivery Systems efficacy and/or surfactants that e.g., drug cytotoxicity can be induced in drug- transporters. For e.g., Surfactants (amphiphilic resistant cell lines by loading nanoparticles with molecules and the drug (doxorubicin) and a P-gP inhibitor hydrophobic groups) can assist drug delivery by (tariquidar). As a logical extension of this concept increasing the fluidity of the cell membrane (for to possible overcome drug resistance, drugs (for e.g., Cremophor® EL), and the mitochondrial e.g., paclitaxel) were encapsulated with an siRNA membrane (Pluronics). This, in turn, may have to silence the MDR1 transcript. Further, this nano- contributed to the change in mitochondrial conjugate was conjugated with biotin, thereby polarity as well as a concentration-dependent converting it into an active drug transport vehicle decrease (poly(alkyl (Kirtane et al., 2013). Alternatively, substrates for cyanoacrylate) can modify the charge properties the uptake transporter (SLC - solute carrier family) of a chemotherapeutics, thereby improving its can be used to improve PK and avoid MDR of uptake Receptor-mediated conventional drugs (Huang et al., 2006). Finally, endocytosis, unlike diffusion, of the nanoparticle- natural products (flavonoids and their synthesized encapsulated drug and its subsequent trafficking synthetic derivatives as efflux inhibitors) can be can occur via endocytic vesicles. This mechanism used in combination with chemotherapeutic can position a higher concentration of the drug drugs to reduce toxicity and improve efficacy closer more (Conseil et al., 1998; Zhang et al., 2004). Also, corroborative evidence is necessary, evidence kaempferol has been shown to be an ABCG2 (for an alteration in the intracelullar distribution inhibitor due to a different mode of uptake) is available for intracellular accumulation of quercetin, thereby nanoparticle-drug providing a mechanistic rationale for the use of in and to the hydroxypropyl) ATP both levels. transport. site of inhibit hydrophilic Polymer action. conjugates (for methacrylamide While e.g., N-(2- (HPMA) – this and contributes combination to therapy the to increased improve adriamycin conjugate). Since late endosomes bioavailability (An et al., 2011). The recurrence of have a lower pH, this different, physiological tumors, property can be exploited to trigger drug release combination), has been attributed, at least in at that site. This aspect can be combined by the part, to the presence of the relatively resistant use sizes cancer stem cells (CSCs) or side population (SP) (mesoporous silica) to further regulate/fine-tune cells that share features with CSCs. Such cells drug release. Use of the aforesaid combination have therapy approach has its limitations in terms of the expression of the P-glycoprotein as well as the PK of the efflux inhibitor altering the PK of the other proteins of the MDR family (MRP). Increased chemotherapeutic drug. It is also important to expression of multiple members of the family is avoid side-effects (toxicities due to the efflux significant and should be borne in mind, since it is inhibitors or the anti-cancer drug inhibiting the known that drugs that bypass p-GP (for e.g., physiological functions of P-gP in normal cells). To nucleotide analogs) can possibly be effluxed by address this problem, nanoparticles encapsulating another transmembrane protein in the same the aforesaid combination of an efflux inhibitor family (for e.g., MRP2 (ABCC2) (Hoffmann et and a chemotherapeutic drug can be used. For al.2004) and may also be overexpressed in a of conjugates of different pore despite been therapy shown to (singly have an and/or in increased Covered in Scopus & Embase, Elsevier Int. J. Drug Dev. & Res., January-March 2015, 7 (1): 127-136 © 2015 Suresh P.K. et al, publisher and licensee IYPF. This is an Open Access article which permits unrestricted noncommercial use, provided the original work is properly cited. Full Length Original Research Paper Page 131 efflux comprising can CSCs. Further, there is evidence in the literature, cells (CSCs). that in certain cases, the evolution of tumors may not follow a hierarchical CSC model (each cell 4. may have an equal chance of becoming MDR - CSCs -Strategies for Targeting tumorigenic) with stochastic genetic/epigenetic CSCs are considered to be the major reservoir for changes resulting in phenotypically similar cells. In cancer relapse as well as the originator of other cases, there can be diverse cells in terms of metastatic cell growth. Their relative resistance, their phenotype and these cells can undergo following a chemotherapeutic drug regimen (part reversible changes, necessitating the need to of the “acquired resistance” phenotype), and accurately identify and possibly quantify CSCs as their MDR well as their subsets. However, it is widely phenotype, has been attributed to the increased accepted that both models need not be mutually expression of drug efflux transporters, apart from exclusive (clonal evolution may be important for the contributions made by alterations in DNA both CSCs and non-CSCs) and an effective repair capabilities and apoptosis (Trumpp and therapeutic strategy would have to target the Wiestler 2008). These aberrations have been CSCs, non-CSCs (large numbers of tumorigenic reported at the membrane, cytosol as well as in at cells) as well as the microenvironment harboring the nuclear levels (Stavrovskaya, 2000). This may both these categories of aberrant cells complement selection- 2015; Vermeulen et al., 2012). Some of these stem pressure-induced (could be related to the hypoxic cells, known as side population cells, have been niche/microenvironment) resistance” identified, due to their differentially high efflux of (Pan et al., 2006). While drug-efflux-mediated Hoechst dye and Rhodamine (substrates of both evasion of apoptosis is an important mechanism, ABCB1 and ABCG2). These cells are relatively other hallmarks of cancer (independence-from quiescent; resistant to chemotherapeutic agents, the need for growth-stimulatory signals - for e.g., apart from being anti-apoptotic (Zhao et al., constitutive EGF/EGFR 2013). This heterogeneity (temporal and/or spatial) proliferation pathway; refractoriness to growth– notwithstanding, the approach to target CSCs, inhibitory adopted important contribution the to development activation signals; of “intrinsic of the increased the angiogenesis- by many, warrants a (Suresh conceptual mediated supply of nutrients to the growing understanding of the approaches taken to target tumor; invasion and metastasis as well as enabling this important set/subset of cancer cells, with replicative immortality) have to be considered for classical examples of each strategy. Further, it can developing/refining the drug cocktail for CSCs. be expected that any drug cocktail developed to Also, the emerging hallmarks (reprogramming of target these relatively resistant, rare cells should the metabolic pathways and the evolution of the be capable of eliminating the more sensitive metabostemness and larger numbers of non-CSC tumorigenic cells. Alarcón 2014; Menendez et al., 2014) as well as Apart from the aforesaid combination therapy the immune evasion mechanisms developed) targeting the efflux inhibitors in cancer cells, (Hanahan and Weinberg 2011) will contribute to inhibiting one of the CSC enzyme (aldehyde drug resistance as well as the outgrowths from dehydrogenase) using drugs (for e.g., all –trans- phenotype (Menendez Covered in Scopus & Embase, Elsevier Int. J. Drug Dev. & Res., January-March 2015, 7 (1): 127-136 © 2015 Suresh P.K. et al, publisher and licensee IYPF. This is an Open Access article which permits unrestricted noncommercial use, provided the original work is properly cited. Page 132 Suresh P.K. et al; ABC transporters in anticancer drug transport – Lessons for Therapy, Drug Development and Delivery Systems subset of recalcitrant, relatively resistant tumor retinoic acid), with nanotechnology-based strategies for improving certain the PK/PD profile of the chemotherapeutic drug chemotherapeutic drugs. This observed chemo- and hence, the dosage regimen. These strategies sensitization was associated with a concomitant can be used to target CSC – reservoirs of relapsing reduction in the levels and activity of the two cancers and the originator of metastatic cancer isozymes of ALDH (ALDH1 and ALDH2) (Arrieta et growth. chemosensitization is of associated such cells to al., 2010). Apart from such approaches, drugs that target the niche (housing the CSCs) as well as those that act on key signaling molecules (for e.g, Acknowledgements The authors would like to profusely thank the important, currently used strategies to combat management MDR using a cocktail of conventional and/or encouragement and infrastructural support, that biopharmaceutical strategies (siRNA) (Di and enabled us to compile this manuscript. for their constant source of Zhao 2015). Further, it was shown that colo-rectal cancer cells with Kras mutations that were References resistant to conventional EGFR therapy could be treated with Notch antagonists (Fischer et al., 2011). These Page 133 decrease antagonist self-renewal could and 1) Al-Assaf AH, Alshatwi AA (2013). 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