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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).
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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
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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
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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,
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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
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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
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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
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Article History: -----------------------Date of Submission: 26-02-2015
Date of Acceptance: 15-03-2015
Conflict of Interest: NIL
Source of Support: NONE
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