Drug Resistance in Leukemia: Remediation by Natural...
Transcript of Drug Resistance in Leukemia: Remediation by Natural...
INTRODUCTION
Cancer is still an enigma and one of the
leading threats to human life, affecting
individuals of all ages and sex. Although
the risk of cancer increases with age, an
estimated 165,000 new cases of
paediatric cancers were reported in 2012.
Besides, cancers are also on the rise in
the developed world. Among different
types, leukemia, the cancer of the early
blood-forming cells, is quite common.
Hematopoetic cancers observed in
paediatric patients constitute leukemias,
lymphomas and myelomas. Lymphomas
are primarily Hodgkin's and non-
Hodgkin's lymphoma. Hodgkin's
lymphoma, identified by the presence of
Reed-Sternberg cells in lymph nodes,
may be classical or nodular lymphocyte-
predominant Hodgkin's disease (nlphd).
On the other hand, Non-Hodgkin's
lymphoma is a rare cancer involving the
lymphatic system, treated by
Key words: Leukemia, drug resistance, phytochemicals, Pgp, MRP.*Corresponding Author: Madhumita Roy, Department of Environmental Carcinogenesis and Toxicology, Chittaranjan National Cancer Institute, 37, S. P. Mukherjee Road, Kolkata – 700026, West Bengal, India.Email: [email protected]
Drug Resistance in Leukemia: Remediation by Natural
Means
Chittaranjan National Cancer Institute, Kolkata – 700026, West Bengal, India
Madhumita Roy*, Apurba Mukherjee, Sutapa Mukherjee and Jaydip Biswas
Leukemia is a common cancer in the paediatric group with good prognosis and the overall survival rate
for leukemia has improved over the years. However, despite the chemopreventive agents and better
diagnostic and therapeutic strategies, novel strategies and approaches shows better prognosis and
overall survival, particularly if detected early. The common modality of haematological malignancy
management is chemotherapy. Although good response is noted early on treatment, resistance to the
chemotherapy is observed later due to the drug resistance, may be due to increased expression of P-
glycoprotein (Pgp) and multidrug resistance protein (MRP1), which may be reversed by inhibitors of the
proteins. However, adverse side effects of the chemotherapeutic agents are a cause of concern in
several patients. Hence, plant derived molecules (phytochemicals) may be considered as an alternative
to the synthetic inhibitors. Phytochemicals possess not only chemopreventive and chemotherapeutic
potential, but also can be used for prevention and reversal of drug resistance. Phytochemicals are
generally nontoxic, economic and minimal adverse effects are observed. Potential phytochemicals may
be used as stand-alone or in combination for cancer treatment.
Review
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Roy et al. 9
chemotherapy. Abnormality in plasma
cells result in myelomas. Paraproteins, a
type of antibodies, are released in
mylomas, which acts as a diagnostic
marker.
Types of Leukemia
Depending on the development of the
disease, leukemia may be acute or
chronic. If not diagnosed or treated in
time, chronic type may convert to acute
leukemia. Myeloid blast (immature) cells
are formed when stem cells mature in the
bone marrow, which on maturity become
red blood cells or platelets or white blood
cells. On the other hand, lymphoid blasts
are formed when the lymphoid stem cells
in the bone marrow matures. They
develop further into T (maturing in the
thymus gland) or B (maturing in the bone
marrow) lymphocytes. Therefore,
myeloid leukemia consists of myeloid
cells, whereas origin of the lymphoid
leukemias is the lymphoid cells.
Broadly, leukemia can be of four
types: Acute Lymphocytic Leukemia
(ALL), Chronic Lymphocytic Leukemia
(CLL), Acute Myeloid Leukemia (AML),
and Chronic Myeloid Leukemia (CML).
In ALL, immature lymphoid cells
proliferate rapidly in the blood. ALL,
although known as childhood leukemia
can also appear in adults. AML (affecting
both children and adults) results because
of the fast growth of myeloid cells.
Lymphoid cells that grow at a lesser rate
lead to CLL, in which adults get affected.
CML majorly affects adults, but there are
incidences in children. There are some
rare forms of leukemias like Hairy Cell
Leukemia, Chronic Myelomonocytic
Leukemia (CMML), Juvenile
Myelomonocytic Leukemia (JMML),
Large Granular Lymphocytic Leukemia
(LGL), and Acute Promeylocytic
Leukemia (APL).
Treatment for Leukemia
Treatment of leukemia and its prognosis
depends on the type, age and general
health of the patient and whether it has
affected the cerebrospinal fluid.
Chemotherapy, immunotherapy and
stem-cell transplantation are the
conventional treatment modalities,
however, they have their own drawbacks.
The widely-used treatment for leukemia
is chemotherapy orally, intravenously or
intrathecally. For acute leukemia,
induction chemotherapy is followed by
intensification chemotherapy, which
ensures removal of residual leukemic
cells that escape the first drug challenge.
In general, maintenance chemotherapy is
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10 Remediation of drug resistance in leukemia
recommended to prevent recurrence.
Apart from chemotherapeutic drugs,
monoclonal antibodies and drugs
targeting specific genes are used.
Surgery may not remove all the cancer
cells which may lead to secondary
growth. Similarly, radiation therapy can
damage the surrounding healthy tissues.
Also, all affected cells are neither visible
by scanning nor can be targeted. Stem-
cell transplantation, modulation of
immune system, including administration
of cytokines and vaccinations are other
treatment strategy.
Complications in Leukemia Therapy
There are many complications/challenges
in treating leukemia. Prognosis is
comparatively better in children than
adults. Due to the treatment regimen,
adverse side effects including nausea,
vomiting, sores in mouth, anaemia,
bruising and bleeding, loss of immune
function, i.e. susceptibility to infections,
fatigue, hair loss or alopecia,
development of infertility occurs. Central
nervous system (CNS) impairment,
growth retardation, infertility, cataracts,
and vulnerability to secondary cancers
are common for children receiving
treatment for acute leukemia. Also, tumor
lysis syndrome, where fast destruction of
the cells occurs during treatment. Graft
vs. Host Disease (GVHD) is a common
phenomenon for those receiving stem
cell transplants where kidney function is
badly affected due to release of excess of
phosphate. Development of resistance to
drugs is another main obstacle affecting
prognosis of cancer.
Mechanisms of Drug Resistance
Most of the cancer cells undergo
apoptosis on treatment with drugs,
however, they can also develop
resistance to drugs. This eventually leads
to failure of treatment. Failure of therapy
in cancer may be attributed to
forbearance to treatment strategies. Drug
resistance may develop with single or
number of structurally different drugs,
with diverse mechanisms of action (Foo
and Michor, 2014). Acquisition of drug
resistance may be inherited or acquired.
Unresponsiveness of malignant growth to
a particular chemotherapeutic drug is
attributed to inherited drug resistance
(Housman et al., 2014). During
treatment, single or multiple drugs are
often used and an individual may
develop resistance during the course of
therapy as acquired resistance.
Several proteins are embedded in the
lipid layer of the cell membrane, which
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plays an active role in transportation of
drugs into the cell. The associated
molecules are adenosine triphosphate-
binding cassette (ABC) transporter and
solute carrier (SLC) transporter
superfamily (Vasiliou et al., 2009). ABC
transporters pump out the chemo-
therapeutic drugs from the cell, i.e. an
efflux transporter, whereas SLC
transporters aid in cellular uptake of the
drugs, i.e. influx transporter. Hence,
increased activity of the efflux
transporter and decreased activity of the
influx transporter contribute to the
development of resistance.
A correlation exists between
development of multidrug resistance
(MDR) and overexpression of drug
efflux transporters of the ATP-binding
cassette (ABC) protein family like P-
glycoprotein (Pgp) and a Multi-drug
resistance-associated protein (MRP).
MRP may be present on the plasma
membrane, endoplasmic reticulum and
Golgi apparatus, which are part of
intracytoplasmic membranes and prevent
the drug from reaching its target.
Cysteine-containing tripeptide gluta-
thione (GSH) influences MRP transport
(Lautier et al., 1996) and inhibition of
Pgp plays a role in drug resistance.
However, pharmacokinetic (PK)
interactions interfere with Pgp inhibitors
(Fojo and Bates, 2003) as revealed by
clinical trials to establish efficacy of Pgp
inhibitors. Compounds need to be
developed with predictable PK effects
resulting in efficient inhibition.
Strategies need to be explored to reverse
drug-resistance and increase sensitivity
to drugs. Certain additional proteins
including lung cancer resistance protein
(LRP) identical to the major vault
protein, contributes to drug resistance.
Vault protein, a 13-MDa ribonucleo-
protein, which functions in nucleo-
cytoplasmic transport, is highly
upregulated in drug resistance. An
association of LRP with leukemia has
been indicated, and over-expression of
LRP may be a good prognostic tool in
AML (Hart et al., 1997). High level of
BCRP (Breast Cancer Resistance
Protein), associated with drug resistance,
has been observed in AML. Normal cells
are protected from the toxic effects of the
drugs by BCRP (Nakanishi and Ross,
2012). Different modalities leading to
drug resistance include drug inactivation,
alteration of drug targets, drug efflux,
DNA damage repair, inhibition of cell
death, EMT, and epigenetic regulation
(Figure 1) (Housman et al., 2014).
Besides, inherent heterogeneity of cancer
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cells may result in innate resistance to
drugs, which is attributed to the stem cell
like properties of a proportion of cancer
cells.
ABC transporter proteins pump drugs
out of cells at the expense of hydrolysis
of ATP (Cho, 2005). The drugs bind to
the substrate binding pockets of these
proteins through hydrogen bonding and
hydrophobic interactions. Drug efflux
occurs when the drug binding site gets
re-oriented from the cytosolic to the
extracellular side of the membrane. This
involves a transition from high to low
drug binding affinity. The efflux is
facilitated by binding of ATP, nucleotide
sandwich dimer formation, ATP
hydrolysis, Pi and ADP dissociation
(Sharom, 2008). Retention of drugs is
important for pharmacological action and
increased efflux leads to development of
resistance (Housman et al, 2014).
MDR1, MRP1, BCRP and LRP play vital
roles in this regard (Gottesman et al.,
2002). MDR1 removes the chemo-
therapeutic drugs which require
metabolic activation for their activity.
The drug interacts with several proteins,
undergoing modification, degradation or
complexing with molecules, leading to
activation and development of drug
resistance (Zahreddine and Borden,
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Figure 1: Different factors leading to emergence of drug resistance.
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2013). Further, alteration in the activity
of Glutathione-S-transferase (GST) or
Cytochrome P450 (CYP) diminishes the
cytotoxicity of the drugs with cancer
cells developing resistance (Michael and
Doherty, 2005). The alterations may be
due to mutations of genes or
perturbations of proteins. Signal
transduction proteins are also associated
with drug activation and alterations in the
processes may render the therapeutic
protocol inefficient (Stavrovskaya,
2000). The chemotherapeutic drugs often
causes damage in the DNA and the
damaged DNA either gets repaired or the
cell undergo apoptosis. However, on
DNA repair and damage reversal, the
cells survive. The efficiency of the drug
is compromised, thus, culminating into
drug resistance. Activation of repair
process may be due to genetic or
epigenetic changes (You and Jones,
2012). Epigenetic changes transmit
through cell division and lead to
alterations in gene expression during
treatment period. Epigenetic regulation
may occur through DNA methylation and
histone modification contributing to the
development of cancer (Kanwala and
Gupta, 2012). Epigenetic mechanisms
impact DNA damage repair genes
including hMLH1, MGMT with
hypermethylation, silencing and
hypomethylation, resulting in over-
expression of the genes (Koutsimpelas et
al., 2012). Cancer progenitor cells are
insensitive to drugs contributing to
relapse and epigenetic modifications are
associated with formation of the
progenitor cells (Sarkar et al., 2013,
Byler et al., 2014).
The aim of chemotherapy is cancer
cell death, through programmed,
regulated and controlled process of cell
death or apoptosis. In malignancy,
antiapoptotic proteins are increased,
resulting in failure of cell death. Besides
autophagy, which maintains cellular
homeostasis also plays a role in drug
resistance (Wilson et al., 2009). The p53
gene, guardian of human genome is
mutated in several cancers, rendering it
non-functional, with consequent evasion
of apoptosis. Deregulation of p53
regulators including caspases, Apaf1
impedes the action of drugs (Soengas et
al., 1999). During development of drug
resistance, GST plays a role via
detoxification and inhibition of the
mitogen-activated protein kinase
(MAPK) pathway (Townsend and Tew,
2003). ERK1/2, PI3K/Akt, STAT, JNK
(Housman et al., 2014), HSP90 (Fukuyo
et al., 2010) and NFB activation and loss
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of PTEN function also contribute to drug
resistance in leukemia cells (Berns et al.,
2007). GSH implicated in this
phenomenon, is directly influenced by c-
jun (Housman et al., 2014). Epidermal
Growth Factor Receptor (EGFR), Protein
Kinase C (PKC) and Ras, Src, Raf, MEK
are activated in cancer and associated
with drug resistance (Housman et al.,
2014). Repair enzymes, for example, O6-
Methylguanine DNA Methyltransferase
(MGMT) and Topoisomerase II
(Housman et al., 2014) and compounds
that perturb cellular calcium level, Pgp,
ABC transporters, increased activity of
sodium pump contribute to drug
resistance (Hoffmann and Lambert,
2014). Metastasis important in cancer
incolves epithelial to mesenchymal
transition (EMT). Signalling process of
differentiation is mandatory for EMT and
drug resistance sets at the advent of the
process (Housman et al., 2014). Relapse
of cancer is often seen after treatment
completion. The cancer stem cells are
constitutively resistant to chemo-
therapeutic agents, mediated by the
transporter proteins and phase II
detoxification enzymes (Housman et al.,
2014). The various mechanisms of drug
resistance of cancer cells are summarized
in Table 1.
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Reversal of Drug Resistance
The chemotherapeutic regimen used in
the treatment of cancer are effective with
adverse side effects and drug resistance.
Several compounds modify, modulate or
reverse drug resistance, via regulation of
Pgp expression. Several compounds
including Verapamil, Cyclosporin,
Quinidine, Tamoxifen, Progesterone, and
Reserpine reverse drug resistance (Inaba
et al., 1981). However, reversal of drug
resistance may be transient (Xia et al.,
2012). Moreover, the molecules show
toxicity and severe side effects. An
alternative approach is use of
phytochemicals for treatment of cancer.
The plant products can be preventive,
beneficial in treatment, increase the
efficacy of conventional drugs and revert
drug resistance (Wang et al., 2012).
Therefore, continuous efforts are being
made to find a better and effective
option.
Phytochemicals in Reversal of Drug
Resistance
A plethora of plant derived components
are known for their anticancer properties.
Products obtained from vegetables,
fruits, herbs and spices can be divided
into various families such as alkaloids,
phenols, phenolic acids, flavonoids,
isoflavones, isothiocyanates, organo-
sulfur compounds, capsaicinoids,
carotenoids, saponins, terpenoids,
coumarin, lignans, glycolipids, vitamins
and phytosterols. The active plant
molecules act as potential agents to
prevent carcinogenesis by inhibiting,
reversing and retarding the process
(Surh, 2003). Apart from chemo-
prevention, they are considered as
suitable candidates for cancer treatment.
Therefore, herbal remedy may be an
option for tackling drug resistance
(Hosseini and Ghorbani, 2015). The
mechanisms of action of some of these
biomolecules are listed (Table 2).
Flavonoids, act as chemical
messengers, physiological regulators,
and cell cycle inhibitors and may
efficiently reverse multidrug resistance
through inhibition of Pgp (Imai et al.,
2004). Two such important flavonoids
eliciting this reversal of drug resistance
function are Quercetin and Kaempferol,
isolated from Chinese herbal medicine
Choerospondiatis (Yanqiu et al., 2011).
Both the flavonoids influence drug
transporter genes responsible for
absorption, distribution, metabolism and
excretion of drugs. Autophagy inducer in
leukemia cells, Apigenin isolated from
Chamomile is a flavonoid and induces
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apoptosis in CML cell line K-562 and
drug resistant K-562 cells (Solmaz et al.,
2014) by G2/M phase and S phase arrest
of the cells. An isoflavone Genistein
derived from soy products is a tyrosine
kinase inhibitor (Naraghi et al., 2000).
Genistein increases the efficiency of
chemotherapeutic agents through
regulation of the transcription factor NF-
κB, which is often activated by
chemotherapeutic drugs (Godwin et al.,
2013). This plant product having
antineoplastic activity has not yet been
reported as a potential agent in drug
reversal (Limtrakul et al., 2005). The
active ingredient of turmeric is curcumin,
which possesses strong anti-cancer
properties, protects development of drug
resistance in CML (Xu et al., 2011).
Minimal expression of mdr1 mRNA and
Pgp is observed in K-562 cells, with
overexpression in drug resistant cells (Fu
et al., 2000). Curcumin prevents drug
resistance by preventing the upregulation
of multidrug resistance proteins Pgp and
MRP1. The prevention of drug resistance
by curcumin is due to modulation of NF-
κB and DNA-binding capability which
regulates the expression of mdr1
(Godwin et al., 2013). Strawberry, apple,
persimmon, grape, onion and cucumber
contain a flavonoid called Fisetin,
capable of reversing drug-resistance by
suppression of Pgp, over-expressed in
drug resistant leukemia cells (Batra and
Sharma, 2013). The role of Fisetin in
reversal of drug resistant leukemia cells
needs further investigations. Peanuts,
pistachios, grapes, red and white wine,
blueberries, cranberries, cocoa and dark
chocolate are rich in a compound called
Resveratrol with diverse health benefits,
including induction of apoptosis in
cancer cells (Tian and Yu, 2015). Both
the intrinsic and extrinsic pathways of
apoptosis are triggered by Resveratrol.
Resveratrol not only shows its anti-
carcinogenic activities, but, it also aids in
reversal of drug-resistance (Can et al.,
2012). For treatment of CML the
conventional drug of choice is tyrosine
kinase inhibitor Imatinib Mesylate (IM),
which inhibits the activity of BCR-ABL
fusion protein, a characteristic feature of
CML (Maekawa et al., 2007), although
resistance to IM may develops in CML
patients. Resveratrol may be considered
as beneficial in CML patients on IM
treatment and in IM resistant cases. In
Adult T-cell Leukemia/Lymphoma
(ATLL) resistance to TRAIL is
commonly observed. BB-1, a
dihydroflavonol from plant Blumea
balsamifera enhances the sensitivity to
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TRAIL, by a p53 independent pathway
(Hasegawa et al., 2006). The commonly
consumed cruciferous vegetables are rich
in Phenethyl isothiocyanate (PEITC),
which exhibits a number of biological
activities. In case of CML, the cytotoxic
activity is due to induction of reactive
oxygen species (ROS), stress and
oxidative damage (Yeh et al., 2014).
PEITC inhibits tumor formation, stalls
metastasis, acts as a chemo-enhancer, and
reverses chemo-resistance (Nachat et al.,
2016). Resistant leukemia cells are
sensitized to the drug by PEITC, has
been observed in other cancers as also
observed for breast, bladder, gastric and
lung cancer. Phenylhexyl isothiocyanate
(PHITC), an isothiocyanate in
cruciferous vegetables, shows synergism
with IM in drug resistant K562 cells. It
is interesting to note that Pgp expression
is not altered by PHITC, however,
reversal of drug resistance is facilitated
by inhibition of P210 (bcr-abl) and its
phosphorylated form (Wu et al., 2013).
Indole-3-Carbinol (I3C), present in
abundance in cruciferous vegetables is
notable for its nutritional value,
particularly anticancer potential. I3C
lowers the expression of Pgp in resistant
leukemia cells, thereby acting as an agent
for regulation of drug resistance (Arora et
al., 2005).
Tea is the most popular beverage
across different countries and among the
different types, green tea is favoured for
health benefits. Green tea polyphenol
Epigallocatechin Gallate (EGCG) is
efficient in drug reversal. EGCG
preferentially attacks cancer cells in
haematopoietic neoplasms. EGCG
sensitizes K-562 cells to Imatinib
Mesylate and also works efficiently on
imatinib-resistant K562 cells. Hence, tea
polyphenols may have a role in reversal
of drug resistance (Davenport et al.,
2010). Diallyltrisulfide, an organosulfur
compound found in allium vegetables
aids in increasing the intracellular
concentration of drugs in leukemia cells
(Choi and Park, 2012). Diallylsulfide,
another derivative of garlic increases
cytotoxicity of drug resistant leukemia
cells (Arora et al., 2004). The calcium
channel blocker Tetrandrine is a bis-
benzylisoquinoline alkaloid, with anti-
inflammatory, immunologic and
antiallergenic properties. The alkaloid,
isolated from the root of Stephania
tetrandra has the capability to inhibit
drug efflux mediated by Pgp, thereby
preventing multi drug resistance.
Tetrandrine is effective in combination
with conventional drugs (Daunorubicin,
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Etoposide and Cytarabine) used in
leukemia (Xu et al., 2006). Other plant
molecules rich in alkaloids, like Matrine
isolated from Sophora alopecuroides aids
in enhanced intracellular accumulation of
doxorubicin in vincristine resistant CML
cell line K-562, thus overcoming drug
resistance (Ding et al., 2004). The Carrot
family is well known for the anticancer
effects. Ligusticum chuangxiong, a
Chinese medicine of the carrot family is
of medicinal values due to the presence
of active phytochemicals, of which
Tetramethylpyrazine is an active
alkaloid. This alkaloid is capable of
reverting drug resistance in HL-60
cancers cells, resistant to Vincristine,
Daunorubicin and Doxorubicin (Tan,
2009). Peimine and Berbamine alkaloids
elicit reversal of drug resistance observed
in vitro in doxorubcin resistant K562
cells by inhibiting Pgp (Hu et al., 1999,
Dong et al., 2004). Rosemarinic acid, a
derivative of Chinese medicinal herb, is
used to treat cancer in the traditional
Chinese medicine. The compound
imparts toxicity to leukemia cell line
with the normal lymphocytes unaffected.
The cytotoxicity of Rosemarinic acid is
due to PARP cleavage, caspase activation
and inhibition of translocation of p65
subunit of NFκB from cytosol to nucleus
(Wang et al., 2014). The active
component of Rosmarinus officinalis L is
Carnosic Acid (CA), an antioxidant
phenolic diterpene notable for its
antioxidative, anti-inflammatory, and
anti-tumor properties. Carnosic Acid
reverts the subcellular distribution of
Adriamycin by reversing Pgp mediated
MDR in drug resistant K-562 cells (Yu et
al., 2008). Celastrol, a pentacyclic
triterpenoid, an isolate from root extracts
of Tripterygium wilfordii showed
anticancer properties (Davenport et al.,
2010). Besides its use in obesity
management, it overcomes MDR in drug
resistance in CML cell. Glycyrrhetinic
acid, a pentacyclic triterpenoid derivative
from the herb liquorice overcomes drug
resistance in HL-60 cells via
programmed cell death induced by CD95
and CD178 signalling pathways
(Pirzadeh et al., 2014). Saponin isolated
from Anemarrhena asphodeloides called
Timosaponin A-III (TAIII) reverses
MDR protein in Adriamycin resistant K-
562 cells (Chen et al., 2016). This was
determined by the expression of Pgp and
MRP1 mRNA by reverse transcription
polymerase chain reaction (RT-PCR) and
western blotting. Inversion of MDR was
also evident in Adriamycin resistant
K562 cells by M. polymorpha derived
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macrocyclic bisbibenzyl plagiochin E
(Shi et al., 2008). Dihydroptychantol A
(DHA), another macrocyclic bisbibenzyl
isolated from the liverwort Asterella
angusta inhibited drug resistance in
Adriamycin resistant K562 cells (Li et
al., 2009).
A class of saponins (glycosides and
triterpene), isolated from roots of the
plant Panax (ginseng) are often used in
traditional medicine (Chai et al., 2010).
Ginsenosides saponins reverts drug
resistance in chronic myelogenous
leukemia cell line K-562, resistance to
Vincristine and Doxorubicin, and acute
pro-myelocytic Vincristine resistant
leukemia cell line HL-60. Saponin
isolated from a mountain plant, Panax
notoginseng (also called tienchi ginseng),
showed ability to reverse drug resistance
in leukemia cell by Pgp inhibition (Chai
et al., 2010). Vitamins play an important
role in reversing drug resistance. Fat
soluble Vitamin D regulates cell growth,
immune function, differentiation and
programmed cell death. Besides, Vitamin
D also aids in reversal of drug resistance
by modulating MDR1 and MRP1 genes
(Yan and Nuriding, 2014). Pgp and
glutathione are inhibited by vitamin D.
Tocopherols and tocotrienols belong to
the fat soluble Vitamin E family, and the
chemopreventive properties of Vitamin E
are attributed to inhibition of ROS
(Nieborowska-Skorska et al., 2013).
Vitamin E inhibits mutations, thus
overcoming drug resistance in CML.
A number of active compounds of
medicinal importance have been obtained
from Terpenoids and phenolic bibenzyls
that confer anticancer properties and may
facilitate reversal of drug resistance in
cancer cells (Dey and Mukherjee, 2015).
Wogonin (5,7-dihydroxy-8-methoxy-
flavone), a product extracted from the
root of Scutellaria baicalensis, aids in
reversal of drug resistance by inhibiting
MRP1, both at the protein and gene
level, in resistant leukemia cells (Wu et
al., 2016). Another traditional medicine
is from Embelia ribes plants, found in
southern part of India, with embelin as an
active ingredient. Besides, it contains an
alkaloid, christembine and other active
ingredients with anticancer potential. In
vitro studies established efficacy of
embelin to increase sensitivity of drug
resistant leukemia K562 cells. Withaferin
A, from Withania somnifera is efficient
in inhibiting NF-κB in drug resistant
CML cell K-562, contributing to reversal
of drug resistance (Lee and Choi, 2016).
Several additional plant molecules, that
overcome drug resistance in a number of
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cancers including leukemia, include
Emodin from fungi of the genera
Aspergillus; Elemene, isolated from
various tropical plants, Ephedrine from
Ephedra sinica, Oridonin; a diterpenoid
from Rabdosia rubescens; alkaloid
Ligustrazine and Tertramethyl pyrazine
from chuanxiong. A unique property of
these compounds is that they show little
effect on drug sensitive cells, but aid in
enhancement of sensitivity in drug
resistant cells, indicating their selective
action on resistant cells. Certain other
plant derived products (Morin, Nobiletin
and Heptamethoxyflavone) are known to
increase drug uptake in drug-resistant
leukemia cells. Certain compounds
modulates reversal of drug resistance,
either with or without involvement of
Pgp. Dauricine, a bisbenzylisoquinoline
alkaloid and Paeonol, a calcium channel
blocker aids in overcoming drug
resistance in leukemia cells by Pgp
independent pathway. (Chai et al., 2010).
The current information on drug
resistance is based on in vivo or in vitro
experimental models. However, to prove
the efficacy of plant derived products,
bench to bedside translation is required
including clinical trials. Homo-
harringtonine, an alkaloid from
Cephalotaxus, effective in treatment of
hematological malignancies has
undergone clinical trials to establish the
efficacy in treatment of CML patients. A
majority of patients showed complete
hematological response (Lucas et al.,
2010). Further trials towards use of
Homoharringtonine in treatment of drug
resistant CML is anticipated. Fritillariae
thunbergii was used to treat acute
leukemia patients (Hu et al., 2004), and
showed reduced number of leukemic
cells in blood forming organs, lower
levels of MDR1 and decreased rate of
recurrence, in drug resistant AML (Li et
al., 2004).
Several herbal formulations indicate
a potential for leukemia, but with
experimental and clinical trials with
studies on a large scale needs to confirm
their use. Chemical composition of the
extracts, active component, with
additional information on storage,
stability, exposure to sun, humidity,
growth condition, harvest season,
formulations, and use as drugs needs to
be confirmed. Generally these plant
biomolecules are safe for human
consumption, but, the safety assessment
needs to be performed. There may be a
handful of subjects who are allergic to
these products. Often drugs are
consumed to address several health
22 Remediation of drug resistance in leukemia
Biomed Res J 2017;4(1):8–27
CONCLUSION
Conventional chemotherapy in leukemia
though remedial, shows side effects,
besides development of drug resistance
with evasion of apoptosis. Acquired
resistance may arise due to a number of
mechanisms. Several plant molecules
(phytochemicals) have anticancer
properties and an active role in reversal
of drug resistance and hence a pivotal
role is anticipated in management of
leukemia.
issues, in this regard it is important to
know if there is any interaction between
these phytochemicals and the drugs
(Firenzuoli and Gori, 2007). Safety of the
formulations for pregnant and lactating
mothers needs attention. Bioavailability
of some of these phytochemicals also
needs to be addressed. For example,
anticancer properties of curcumin is well
known, but its bioavailability is poor.
However, it can be improved by nano
formulation, use of piperine, extract of
the plant Piper nigrum (Roy et al., 2011).
REFERENCES
Arora A, Seth K, Kalra N, Shukla Y. Modulation
of P-Glycoprotein-Mediated Multidrug
Resistance in K562 Leukemic Cells by
Indole-3-Carbinol. Toxicol Appl Pharmacol
2005; 202:237–243.
Arora A, Seth K, Shukla Y. Reversal of P-
Glycoprotein-Mediated Multidrug Resistance
by Diallyl Sulfide in K562 Leukemic Cells
and in Mouse Liver. Carcinogenesis 2004;
25(6):941-949.
Batra P, Sharma AK. Anti-cancer potential of
flavonoids: recent trends and future
perspectives. 3 Biotech 2013; 3(6):439–459.
Berns K, Horlings H, Hennessy B, Madiredjo M,
Hijmans M, Beelen K, et al. A functional
genetic approach identifies the PI3K pathway
as a major determinant of trastuzumab
resistance in breast cancer. Cancer Cell 2007;
12:395–402.
Byler S, Goldgar S, Heerboth S, Leary M,
Housman G, Moulton K, Sarkar S. Genetic
and epigenetic aspects of breast cancer
progression and therapy. Anticancer Res
2014; 34:1071–1077.
Can G, Cakir Z, Kartal M, Gunduz U, Baran
Y. Apoptotic Effects of Resveratrol, a Grape
Polyphenol, on Imatinib-Sensitive and
Resistant K562 Chronic Myeloid Leukemia
Cells. Anticancer Research 2012;
32(7):2673-2678.
Chai S, To KKW, Lin G. Circumvention of multi-
drug resistance of cancer cells by Chinese
herbal medicines. Chin Med 2010; 5: 26.
Chen JR, Jia XH, Wang H, Yi YJ, Wang JY, Li
YJ. Timosaponin A-III reverses multi-drug
resistance in human chronic myelogenous
leukemia K562/ADM cells via
downregulation of MDR1 and MRP1
expression by inhibiting PI3K/Akt signaling
pathway. Int J Oncol 2016; 48(5):2063-2070.
Cho CH. ABC transporters as multidrug
resistance mechanisms and the development
23Roy et al.
Biomed Res J 2017;4(1):8–27
of chemosensitizers for their reversal. Cancer
Cell Int 2005; 5: 30.
Choi YH, Park HS. Apoptosis induction of U937
human leukemia cells by diallyl trisulfide
induces through generation of reactive
oxygen species. J Biomed Sci 2012; 19:50.
Davenport A, Frezza M, Shen M, Yubin G, Huo
C, Chan TH, Dou QP. Celastrol and an
EGCG pro-drug exhibit potent
chemosensitizing activity in human leukemia
cells. Int J Mol Med 2010; 25(3):465–470.
Dey A, Mukherjee A. Therapeutic potential of
bryophytes and derived compounds against
cancer. J Acute Dis 2015; 4(3):236-248.
Ding YF, Xie X, Zhao JY, Yang PM. Reversal of
adriamycin resistance by matrine in leukemia
multidrug resistance cell line K562/ADM. J
Dalian Med Univ 2004; 26(4):256–258, 279.
Dong Q, Zheng S, Xu R, Lu Q, He L. Study on
effect of berbamine on multidrug resistance
leukemia K562/Adr cells. Chin J Integr
Tradit West Med 2004; 24(9):820–822.
Firenzuoli F and Gori L. Herbal Medicine Today:
Clinical and Research Issues. Evid Based
Complement Alternat Med 2007; 4(Suppl 1):
37–40.
Fojo T, Bates S. Strategies for reversing drug
resistance. Oncogene 2003; 22:7512–7523.
Foo J, Michor F. Evolution of acquired resistance
to anti-cancer therapy. J Theor Biol 2014;
355:10–20.
Fu JX, Wang W, Cen JN, Jian-yong L, Chang-
geng R, Zi-xing C. Retroviral mediated
efficient transfer and expression of multiple
drug resistance gene to human leukemia
cells. Chin J Cancer Res 2000; 12:120-124.
Fukuyo Y., Hunt C.R., Horikoshi N.
Geldanamycin and its anticancer activities.
Cancer Lett 2010; 290:24–35.
Godwin P, Baird AM, Heavey S, Barr MP,
O'Byrne KJ, Gately K. Targeting nuclear
factor-kappa B to overcome resistance to
chemotherapy. Front Oncol 2013; 3:120.
Gottesman MM, Fojo T, Bates SE. Multidrug
resistance in cancer: Role of ATP-dependent
transporters. Nat. Rev. Cancer 2002;
2:48–58.
Hart SM, Ganeshaguru K, Scheper RJ, Prentice
HG, Hoffbrand AV, Mehta AB. Expression of
the human major vault protein LRP in acute
myeloid leukemia. Exp Hematol 1997;
25:1227–1232.
Hasegawa H, Yamada Y, Komiyama K,
Hayashi M, Ishibashi M, Yoshida T, Sakai
T, et al. Dihydroflavonol BB-1, an extract of
natural plant Blumea balsamifera, abrogates
TRAIL resistance in leukemia cells. Blood
2006; 107:679-688.
Hoffmann EK, Lambert IH. Ion channels and
transporters in the development of drug
resistance in cancer cells. Philos Trans R Soc
Lond B Biol Sci 2014; 369(1638):20130109
Hosseini A, Ghorbani A. Cancer therapy with
phytochemicals: evidence from clinical
studies. Avicenna J Phytomed 2015;
5(2):84–97.
Housman G, Byler S, Heerboth S, Lapinska K,
Longacre M, Snyder N, Sarkar S. Drug
resistance in cancer: An overview. Cancers
(Basel) 2014; 6(3):1769–1792.
Hu HW, Zheng HX, Qi J, Hou L, Zuo MH, Chen
XY, Sun YL, et al. Study of reversing multi-
drug resistant by Peimine. Chin J Hem 1999;
20(12):650–651.
Hu KW, Chen XY, Zuo MH, Hou L, Sun Z, Li Z,
et al. Fritillaria thunbergii powder
24 Remediation of drug resistance in leukemia
Biomed Res J 2017;4(1):8–27
overcomes drug resistance of acute leukemia
patients. China J Tradit Chin Med Pharm
2004;19:68–70.
Imai Y, Tsukahara S, Asada S, Sugimoto Y.
Phytoestrogens/flavonoids reverse breast
cancer resistance protein/ABCG2-mediated
multidrug resistance. Cancer Res 2004;
64(12):4346-4352.
Inaba M, Fujikura R, Tsukagoshi S, Sakurai Y.
Restored in vitro sensitivity of adriamycin-
and vincristine-resistant P388 leukemia with
reserpine. Biochemical Pharmacology 1981;
30(15):2191–2194.
Kanwala R, Gupta S. Epigenetic modifications
in cancer. Clin Genet 2012; 81(4):303–311.
Koutsimpelas D, Pongsapich W, Heinrich U,
Mann S, Mann WJ, Brieger J. Promoter
methylation of MGMT, MLH1 and
RASSF1A tumor suppressor genes in head
and neck squamous cell carcinoma:
Pharmacological genome demethylation
reduces proliferation of head and neck
squamous carcinoma cells. Oncol Rep 2012;
27(4):1135–1141.
Lautier D, Canitrot Y, Deeley RG, Cole SPC.
Multidrug resistance mediated by the
multidrug resistance protein (MRP) gene.
Biochem Pharmacol 1996; 52:967–977.
Lee IC, Choi BY. Withaferin-A – A natural
anticancer agent with pleitropic mechanisms
of action. Int J Mol Sci 2016;17(3):290.
Li W, Hu KW, Su W, Sun YL, Chen XY, Liang B.
Clinical trial of Fritillaria thunbergii Bulb
powder for reversing multidrug resistance in
the patients with acute leukemia. J Beijing
Univ Tradit Chin Med 2004;27:63–65.
Li X, Sun B, Zhu CJ, Yuan HQ, Shi YQ, Gao J,
Li SJ, et al. Reversal of p-glycoprotein-
mediated multidrug resistance by
macrocyclic bisbibenzyl derivatives in
adriamycin-resistant human myelogenous
leukemia (K562/A02) cells. Toxicol In Vitro
2009; 23(1):29-36.
Liang XJ, Chen C, Zhao Y, Wang PC.
Circumventing tumor resistance to
chemotherapy by nanotechnology. Methods
Mol Biol 2010; 596: 467–488.
Limtrakul P, Khantamat O, Pintha K. Inhibition
of P-glycoprotein function and expression by
kaempferol and quercetin. J Chemother
2005; 17(1):86–95.
Lucas DM, Still PC, Pérez LB, Grever MR,
Kinghorn AD. Potential of plant-derived
natural products in the treatment of leukemia
and lymphoma. Curr Drug Targets
2010;11(7):812–822.
Maekawa T, Ashihara E, Kimura S. The BCR-
ABL tyrosine kinase inhibitor imatinib and
promising new agents against Philadelphia
chromosome-positive leukemias. Int J Clin
Oncol 2007;12: 327-340.
Michael M, Doherty MM. Tumoral drug
metabolism: Overview and its implications
for cancer therapy. J. Clin. Oncol 2005;
23:205–229.
Nachat A, Turoff-Ortmeyer S ,Liu C, McCulloch
M. PEITC in end-stage B-cell
prolymphocytic leukemia: Case report of
possible sensitization to salvage R-CHOP.
Perm J 2016; 20(2):74–80. Nakanishi T, Ross DD. Breast cancer resistance
protein (BCRP/ABCG2): its role in
multidrug resistance and regulation of its
gene expression. Chin J Cancer 2012;
31(2):73–99.
Naraghi S, Khoshyomn S, DeMattia JA, Vane
25Roy et al.
Biomed Res J 2017;4(1):8–27
DW. Receptor tyrosine kinase inhibition
suppresses growth of pediatric renal tumor
cells in vitro. J Pediatr Surg 2000;
35(6):884–890.
Navin N, Krasnitz A, Rodgers L, Cook K, Meth J,
Kendall J, Riggs M, et al. Inferring tumor
progression from genomic heterogeneity.
Genome Res 2010; 20:68–80. Nieborowska-Skorska M, Hoser G, Hochhaus A,
Stoklosa T, Skorski T. Anti-oxidant vitamin
E prevents accumulation of imatinib-resistant
BCR-ABL1 kinase mutations in CML-CP
xenografts in NSG mice. Leukemia 2013;
27(11):2253–2254. Pirzadeh S, Fakhari S, Jalili A, Mirzai S,
Ghaderi B, Haghshenas V. Glycyrrhetinic
acid induces apoptosis in leukemic HL60
cells through upregulating of CD95/CD178.
Int J Mol Cell Med 2014; 3(4):272–278.
Ross DD. Novel mechanisms of drug resistance
in leukemia. Leukemia 2000; 14:467-473.
Roy M, Sinha D, Mukherjee S, Biswas J.
Curcumin prevents DNA damage and
enhances the repair potential in a chronically
arsenic exposed human population in West
Bengal, India. Eur J Cancer Prev 2011;20:
123–131.
Sarkar S, Horn G, Moulton K, Oza A, Byler S,
Kokolus S, Longacre M. Cancer
development, progression and therapy: An
epigenetic overview. Int. J. Mol. Sci 2013;
14:21087–21113.
Sharom FJ. ABC multidrug transporters:
structure, function and role in
chemoresistance. Pharmacogenomics 2008;
9(1):105–127.
Shi YQ, Qu XJ, Liao YX, Xie CF, Cheng YN, Li
S, Lou HX. Reversal effect of a macrocyclic
bisbibenzyl plagiochin E on multidrug
resistance in adriamycin-resistant K562/A02
cells. Eur J Pharmacol 2008; 584(1):66-71.
Soengas MS, Alarcón RM, Yoshida H, Giaccia
AJ, Hakem R, Mak TW, Lowe SW. Apaf-1
and caspase-9 in p53-dependent apoptosis
and tumor inhibition. Science 1999;
284:156–159.
Solmaz S, Adan Gokbulut A, Cincin B, Ozdogu
H, Boga C, Cakmakoglu B, Kozanoglu I, et
al. Therapeutic potential of apigenin, a plant
flavonoid, for imatinib-sensitive and resistant
chronic myeloid leukemia cells. Nutr Cancer
2014; 66(4):599-612.
Stavrovskaya AA. Cellular mechanisms of
multidrug resistance of tumor cells.
Biochemistry (Mosc.) 2000; 65:95–106.
Surh YJ. Cancer chemoprevention with dietary
phytochemicals. Nat Rev Cancer 2003;
3(10):768-780.
Tan Z. Neural protection by naturopathic
compounds - an example of
tetramethylpyrazine from retina to brain. J
Ocul Biol Dis Infor 2009; 2(2):57–64.
Tian H, Yu Z. Resveratrol induces apoptosis of
leukemia cell line K562 by modulation of
sphingosine kinase-1 pathway. Int J Clin Exp
Pathol 2015; 8(3):2755–2762.
Townsend DM, Tew KD. The role of glutathione-
S-transferase in anticancer drug resistance.
Oncogene 2003; 22:7369–7375.
Vasiliou V, Vasiliou K, Nebert DW. Human ATP-
binding cassette (ABC) transporter family.
Hum Genomics 2009; 3(3):281–290. Wang H, Oo Khor T, Shu L, Su Z, Fuentes F,
Lee JH, Tony Kong AN. Plants against
cancer: A review on natural phytochemicals
in preventing and treating cancers and their
26 Remediation of drug resistance in leukemia
Biomed Res J 2017;4(1):8–27
druggability. Anticancer Agents Med Chem
2012; 12(10):1281–1305.
Wilson TR, Johnston PG, Longley DB. Anti-
apoptotic mechanisms of drug resistance in
cancer. Curr Cancer Drug Targets 2009;
9(3):307-319.
Wu RJ, Huang YQ, Ma XD. Effect of
phenylhexyl isothiocyanate on drug-
resistance to imatinib in K562/G01 cell line.
Zhonghua Xue Ye Xue Za Zhi 2013;
34(2):149-152.
Wu X, Zhang H, Salmani JMM, Fu R, Baoan
Chen B. Advances of wogonin, an extract
from Scutellaria baicalensis, for the
treatment of multiple tumors Onco Targets
Ther 2016; 9:2935–2943.
Xia Q, Wang ZY, Li HQ, Diao YT, Li XL,
Cui Ji, Chen XL, et al. Reversion of P-
glycoprotein-mediated multidrug resistance
in human leukemic cell line by diallyl
trisulfide. Evid Based Complement Alternat
Med 2012; 2012: 719805
Xu D, Tian W, Shen H. Curcumin prevents
induced drug resistance: A novel function?
Chin J Cancer Res 2011; 23(3):218–223.
Xu WL, Shen HL, Ao ZF, Chen BA, Xia W, Gao
F, Zhang YN. Combination of tetrandrine as
a potential-reversing agent with
daunorubicin, etoposide and cytarabine for
the treatment of refractory and relapsed acute
myelogenous leukemia. Leuk Res 2006;
30(4):407–413.
Yan M, Nuriding H. Reversal effect of vitamin D
on different multidrug-resistant cells. Genet
Mol Res 2014; 13(3):6239-6247.
Yanqiu H, Linjuan C, Jin W, Hongjun H,
Yongjin S, Guobin X, Hanyun R. The
effects of quercetin and kaempferol on
multidrug resistance and the expression of
related genes in human erythroleukemic
K562/A cells. Afr J Biotechnol 2011;10(62):
13399-13406.
Yeh YT, Yeh H, Su SH, Lin JS, Lee KJ, Shyu
HW, Chen ZF, et al. Phenethyl
isothiocyanate induces DNA damage-
associated G2/M arrest and subsequent
apoptosis in oral cancer cells with varying
p53 mutations. Free Radic Biol Med 2014;
74:1-13.
You JS, Jones PA. Cancer genetics and
epigenetics: Two sides of the same coin?
Cancer Cell 2012; 22(1):9–20.
Yu XN , Chen XL, Li H, Li XX, Li HQ, Jin
WR. Reversion of P-glycoprotein-mediated
multidrug resistance in human leukemic cell
line by carnosic acid. Chin J Physiol 2008;
51(6):348-356.
Zahreddine H, Borden KLB. Mechanisms and
insights into drug resistance in cancer. Front
Pharmacol 2013;4:28.
27Roy et al.
Biomed Res J 2017;4(1):8–27