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

Biomed Res J 2017;4(1):8–27

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

Biomed Res J 2017;4(1):8–27

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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Biomed Res J 2017;4(1):8–27

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,

12

Figure 1: Different factors leading to emergence of drug resistance.

Remediation of drug resistance in leukemia

Biomed Res J 2017;4(1):8–27

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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Biomed Res J 2017;4(1):8–27

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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Biomed Res J 2017;4(1):8–27

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

21Roy et al.

Biomed Res J 2017;4(1):8–27

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


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).

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