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Efflux pumps are omnipresent in almost all types of
cells. They participate in the transportation of a wide range of important
molecules across the cell membrane. They play primordial roles in
detoxification of the cell by disposing off unwanted materials. Since tumor
cells emerge from normal cells as a result of mutation, they carry with them
the genes coding for the efflux pumps. These efflux pumps are overexpressed by
cancer cells. They defend the cancer cells against chemotherapy by actively
pumping out the drug molecules that have incurred into the cytoplasm. This
leads to drug resistance, which is the major cause for low efficiency of most
of the chemotherapeutic drugs. Although many efflux pump inhibitors have been
developed, none of them has been clinically approved because of their lack in
specificity, which causes them to incur into the normal cells leading to many
adverse effects. Moreover, with time, the cancer cells develop resistance
against these inhibitors. RNAi mediated gene silencing proved to be effective
in silencing the MDR genes under in vitro
conditions. However, they prove to be inefficient under in vivo trials due to the lack of a proper transport vector that
will be able to transport the pre-interfering RNAs specifically to the tumor
site while keeping the normal cells intact. Many oncolytic viruses have been
identified and genetically engineered to specifically infect a wide range of
tumor cells. This article proposes the use of genetically modified oncolytic
viruses as transport vectors for the pre-interfering RNAs to solve the above
problems. The strategies proposed in this article can be employed to specifically
target the MDR genes present in cancer cells, while keeping the normal cells
untouched and can be used adjunct to chemotherapy to make it efficacious.
Keywords: RNAi,
Efflux pumps, Chemotherapy
BACKGROUND
Abnormal cell division as a result of
mutation leads to cancer. Today, it is one of the leading causes of mortality
globally, leading to 8.8 million deaths every year [1]. In a global survey
carried out in 2015, 90.5 million people were said to suffer from cancer, which
increases by 14.1 million every year and this rate is expected to surpass 20
million by the end of 2025 [2,3]. The different treatments involved in cancer
include chemotherapy, immune therapy, radiation therapy and surgery [4,5].
However, the most widely used therapies against cancer are chemotherapy and
radiation therapy [6]. It is evident that with the passage of time the cancer
cells become more virulent and their resistance to chemotherapy increase [7].
The increase in resistance of the cancer cells against chemotherapeutic drugs
can be attributed to the overexpression of Multidrug Resistance efflux pumps.
Since the tumor cells emerge from normal
cells as a result of mutation, they carry with them the genes coding for the
Efflux pumps. An over-expression of efflux pump proteins is evident in a wide
range of cancer cells [25-31]. The cancer cells overexpress efflux pumps, which
defend them against chemotherapeutic drugs by actively pumping them out of the
cell, thus reducing their intracellular concentration. The efflux pumps belong
to the ABC (ATP binding cassette) transporter family which utilizes the energy
obtained from ATP hydrolysis for the transport of different molecules. The most
extensively expressed members of the ABC family involved in Multidrug
Resistance are transport proteins ABCB1, ABCC1 and ABG2 [32].
In addition, some of the efflux transporter
proteins also act as MHCs (major histocompatibility complex) and play
regulatory roles in cell signaling [33]. Several members of the ABC transporter
family have been depicted to be involved in evading apoptosis and inducing
proliferation of the tumor cells. For example, transport proteins ABCB1 and
ABCC1 play anti-apoptotic roles in tumor cells by delaying response to
apoptotic signals [34-36]. Similarly, transport proteins ABCC1, ABCC4 and ABCG2
bolster proliferation in cancer cells [37-39].
NEED FOR A TRANSPORT
VEHICLE
Over the years many researches have been
carried out in developing drugs targeting the efflux pumps, to be used adjunct
to chemotherapy. Many inhibitors have been developed against the multidrug
resistance efflux pumps such as quinine, quinidine, verapamil, cyclosporin,
PSC-833, MS-209 and others [32]. However, they proved to be disappointments with
very limited rates of clinical success [32,40-46]. Most of them cause drug
related adverse effects due to the lack of specificity, by also damaging the
efflux pumps that are present on normal cells [47].
Efforts to silence the MDR genes have already
been carried out using different molecular biology tools such as antisense
therapy, ribozyme therapy and RNA interference [48-50]. RNA interference via
Small interfering RNA and short hairpin RNA designed to inactivate the MDR
genes proved to be quite efficient in abating drug resistance in cancer cells
[51,52]. Although RNA interference is an efficient technique for gene silencing
under in vitro conditions, it fails
to meet the expectations when subjected to in
vivo due to many factors such as the low bioavailability of the RNA
molecules at the target site, as most of them get excreted from the body
through urine, many are destroyed due to nuclease activity and the others fail
to enter the cell due to their negative charge and large size [53-55]. In
addition, many molecules that manage to successfully pass through the membrane
through endocytosis get degraded inside the endosome before reaching the
cytoplasm [56]. Moreover, using a vector that cannot unload the pre-interfering
RNA molecules specifically at the tumor site may abate the expression of efflux
pumps in normal cells leading to many adverse effects in the body. The above
factors mark the need for a vector that can safely transport the RNA molecules
to their target site [51,57-60]. Using oncolytic viruses as transport systems
for the pre-interfering RNA molecules can solve these problems.
EMPLOYING ONCOLYTIC
VIRUSES TO SILENCE THE MULTIDRUG RESISTANCE GENES VIA RNA INTERFERENCE
Tumor cells are formed as a result of
mutation in normal cells which gives them the ability to evade immune
responses, to proliferate limitlessly and to evade apoptosis. This makes them
an interesting target for viruses to grow in. Some oncolytic viruses exist
naturally. However, most of them are genetically engineered to make them specific
to cancer cell. Some extensively employed oncolytic viruses are Adenovirus,
Chicken anemia virus, Parvovirus, Herpes Simplex virus and Newcastle disease
virus [61].
The upcoming topics propose the use of
Oncolytic viruses in silencing the MDR genes:
Using viral shells
as transport vehicles for pre-interfering RNAs
Certain protein receptors are overexpressed
on the surfaces of tumor cells. They serve as the entry ligands for many
viruses. For example, the intra-cellular adhesion molecule-1 (ICAM-1) and decay
accelerating factor (DAF) which serve as entry receptors for coxsackievirus A21
are over expressed by certain cancer cells [62,63]. Similarly, human ovarian
cancer cells overexpress α2β1 integrin which serves as the entry receptor for
echovirus type 1 [64]. The viruses whose entry receptors are over expressed by
cancer cells can be exploited for selectively targeting the tumor cells [61].
This targeting strategy is called transductional targeting.
In case of enveloped viruses, the viral shell
comprises of the envelope and the capsid, whereas, in case of non-enveloped
viruses it comprises only of the viral capsid. Since, the surface proteins
present on viral shells are involved in the transductional targeting of tumor
cells; they can be used as transport vehicles for safely transferring the
pre-interfering RNAs to the cancer cell, without causing them to intervene into
normal cells.
Only the viruses whose entry receptors are
overexpressed by the cancer cells can be chosen for this strategy. The part of
their genome coding for the capsid, envelope and other associated proteins
should be isolated, amplified and expressed in a protein expression system. The
proteins formed will then self-assemble to form functional viral shells lacking
any genetic material [65-71]. Baculo virus expression system is the most widely
used protein expression system for this purpose [72]. At present, many
virus-like particles lacking genetic material, that mimic the original virus
have being developed using this method, to be used as vaccines to stimulate
humoral and cellular immunity [65-80].
Step 1 depicts the attachment of the VLP to
the cancer cell as a result of ligand-receptor binding. This interaction causes
the uptake of the VLP through endocytosis as depicted in step 2. On entering
the cancer cell, the VLP will lyse, freeing the RNA molecules into the
cytoplasm as in step 3. In step 4 the RNA molecules are cleaved by dicer to
form short interfering RNAs. These small interfering RNAs separate into guide
RNA and passenger RNA. The guide RNA combines with argonaute and other
associated proteins to form the RISC complex which then binds with the target
mRNA, leading to its inactivation as depicted in step 5.
The virus like particles on being injected
will get dispersed throughout the body though blood. On reaching the tumor
cells, the viral receptors will interact with the receptors overexpressed on
the surface of tumor cells leading to its attachment [83]. The clustering of
receptors will give rise to a signaling cascade which will initiate the uptake
of the virus like particle through endocytosis or macro pinocytosis [83]. On
entering the cell, the viral capsids will dissolve, releasing the
pre-interfering RNA molecules into the cytoplasm. These exogenous dsRNAs or
shRNAs will activate the ribonuclease protein Dicer present in the cytoplasm, which
will cleave the double stranded or hairpin RNAs to form short stretches of
double stranded RNA about 25 bp long [84]. These short double stranded RNAs,
also called short interfering RNA will then unwind, giving rise to two short
single stranded RNAs called passenger and guide RNA, respectively. The
passenger RNA will degenerate, whereas the guide RNA will get loaded up on an
Argonaute protein which will then bind with the target mRNA to form the
RNA-induced silencing complex (RISC) [85]. The complex formed will block the
mRNA from getting translated [86]. The RISC complex can also induce the
Argonaute protein “slicer” to cleave the target mRNA and in this way the
expression of the target gene can be attenuated to a great extent [87].
Using oncolytic viruses
to carry out DNA vector based RNAi
Although the previously described strategy
sounds promising, it can be surmised to carry some drawbacks. Firstly, the
targeting strategy is limited to transductional targeting and only a few types
of cancer cells have been known till date, to overexpress viral entry
receptors. Secondly, the proposed virus like particles are not capable of
self-replication, they need to be synthesized manually which may lead to an
increase in their production cost.
Creating a self-replicable genetically
modified DNA virus or a retrovirus, that will be able to replicate inside a
wide range of cancer cells and will be to produce pre-interfering RNAs
naturally through transcription can help to counter the problems associated
with the previous strategy.
Firstly, the virus should be made
nonpathogenic by attenuating its harmful genes. Then, based on the requirement,
the virus should be made cancer cell specific by genetically modifying it in
accordance with any of the following strategies:
Proapoptotic
signaling: Viral
intrusion into a normal cell can trigger apoptotic signaling cascade which can
bring about many morphological and biochemical changes leading to cell death,
thus preventing viral replication [88,89]. Some viruses can synthesize certain
proteins which can inhibit apoptotic signaling thus providing them enough time
to replicate [90]. However, cancer cells generally have a defective apoptotic
pathway [91]. If the viral genes coding for the anti-apoptotic proteins are
mutated then the resulting virus will fail to replicate inside normal cells due
to its inability to inhibit the virus triggered apoptotic pathway [92].
However, it will be able to grow inside cancer cells. For example, Onyx-15, a genetically modified
adenovirus with attenuated Eb1 gene can grow selectively in p53 deficient
cancer cells [93].
Transcriptional
targeting: There
are certain essential viral genes that are necessary for viral replication.
Placing these genes under the regulation of tumor specific promoter can make
the virus tumor specific by seizing its ability to replicate under non-tumor
environment [94]. Hence the viruses will only be able express its vital genes
and replicate it inside tumor cells.
Translation
targeting: A
virus infected cell produces Type I IFN (interferon) which ceases protein
synthesis in its neighboring cells thus making them unfit for viral infection
[95]. Engineering viruses to initiate a more potent IFN response in normal
cells will prevent the viruses from spreading into its surrounding cells [90].
However, as the cancer cells have a defective IFN pathway the genetically
modified viruses will fail to initiate an IFN response in cancer cells thus
permitting viral replication inside them. Some viruses can block IFN signaling
by encoding certain proteins that can inhibit the IFN signaling pathway [96].
Mutating the IFN inhibiting genes can prevent the viruses from replicating in
normal cells [90]. On the other hand, the virus will be able to replicate in
cancer cells as they have a defective IFN signaling pathway which cannot
suppress viral replication [90].
The gene suppression strategy used here would
be based on DNA vector based RNAi technology [88]. After the virus has been
made cancer cell specific, the next step involves constructing a gene which on
transcription will give rise to shRNAs, complementary to the target gene. The
gene should consist of a promoter followed by two complementary sequences
separated by a short non-homologous spacer DNA [88]. The two complementary
sequences should be made in accordance with the sequence of the mRNA to be
silenced. This gene should then be integrated into the genome of the oncolytic
virus.
On being subjected to in vivo trials, the genetically modified virus will fail to
proliferate inside normal cells. However, on infecting a cancer cell it will be
able to replicate itself as well as transcribe the shRNAs which will then form
RISC complex with the target mRNA and degrade it using the same procedure that
was stated earlier. This will diminish the expression of Multidrug Resistance
efflux pumps in the viral infected tumor cells.
The use of genetically engineered DNA viruses
and retroviruses offers a wide range of targeting strategies to be employed to
target a broad range of cancer cells. Since the viruses are self-replicable, it
will be easy to clone them in cancer cell cultures which will also reduce their
production cost.
CONSEQUENCES
The strategies proposed in this article can
be used to abate the expression of Multidrug Resistance efflux pumps in cancer
cells. Using the proposed strategy, adjunct to chemotherapy will make it more
effective. In the absence of efflux pumps, the cancer cells will fail to defend
themselves against the anti-cancer drugs. Hence the chemotherapeutic drugs will
be able to eliminate the cancer cells without much difficulty. This strategy
can also be used to target other important genes expressed in cancer cells that
are also common to normal cells.
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