Emblica officinalis Gaertn), a wonder berry in the

Amla (Emblica officinalis Gaertn), a wonder berryin the treatment and prevention of cancerManjeshwar Shrinath Baliga and Jason Jerome Dsouza

Emblica officinalis Gaertn. or Phyllanthus emblica Linn,

commonly known as Indian gooseberry or amla, is arguably

the most important medicinal plant in the Indian traditional

system of medicine, the Ayurveda. Various parts of the

plant are used to treat a range of diseases, but the most

important is the fruit. The fruit is used either alone or in

combination with other plants to treat many ailments such

as common cold and fever; as a diuretic, laxative, liver tonic,

refrigerant, stomachic, restorative, alterative, antipyretic,

anti-inflammatory, hair tonic; to prevent peptic ulcer and

dyspepsia, and as a digestive. Preclinical studies have

shown that amla possesses antipyretic, analgesic,

antitussive, antiatherogenic, adaptogenic, cardioprotective,

gastroprotective, antianemia, antihypercholesterolemia,

wound healing, antidiarrheal, antiatherosclerotic,

hepatoprotective, nephroprotective, and neuroprotective

properties. In addition, experimental studies have shown

that amla and some of its phytochemicals

such as gallic acid, ellagic acid, pyrogallol, some

norsesquiterpenoids, corilagin, geraniin, elaeocarpusin,

and prodelphinidins B1 and B2 also possess antineoplastic

effects. Amla is also reported to possess radiomodulatory,

chemomodulatory, chemopreventive effects, free radical

scavenging, antioxidant, anti-inflammatory, antimutagenic

and immunomodulatory activities, properties that are

efficacious in the treatment and prevention of cancer. This

review for the first time summarizes the results related to

these properties and also emphasizes the aspects that

warrant future research to establish its activity and

utility as a cancer preventive and therapeutic drug in

humans. European Journal of Cancer Prevention

20:225–239 �c 2011 Wolters Kluwer Health | Lippincott

Williams & Wilkins.

European Journal of Cancer Prevention 2011, 20:225–239

Keywords: amla, anticancer, chemomodulation, chemoprevention, Emblicaofficinalis, Phyllanthus emblica, radiation protection

Father Muller Medical College, Kankanady, Mangalore, Karnataka, India

Correspondence to Manjeshwar Shrinath Baliga, PhD, Research andDevelopment, Father Muller Medical College, Father Muller Hospital Road,Kankanady, Mangalore, Karnataka 575003, IndiaTel: + 91 824 2238331; fax: + 91 824 2437402/2436352;e-mail: [email protected]

Received 6 September 2010 Accepted 14 December 2010

IntroductionDespite all the advances in medical sciences, cancer, a

disease as old as humankind, is globally a major health

problem (Arora, 2010). Recent reports from the Interna-

tional Agency for Cancer Research indicate that in 2008,

approximately 12.7 million new cancer cases and 7.6

million cancer deaths occurred and of these, 56% of all

new cancer cases and 63% of cancer deaths were in the

less developed regions of the world (Ferlay et al., 2010).

Projections are that by 2020, the incidence of cancer will

increase three-fold, and that there will be a dispropor-

tionate rise in cancer cases and deaths from the develop-

ing countries that have limited resources to tackle the

problem (Are et al., 2010).

Conventionally, when localized, cancer may be treated

with either surgery (if operable), or with ionizing radia-

tion (when inoperable), or by combining both these

modalities. However, in the advanced stage, and more

importantly, when metastasis is observed, the use of cyto-

toxic chemotherapeutic agents is obligatory (DeVita et al.,2004). Unfortunately, the use of chemotherapy and ioniz-

ing radiation is associated with deleterious side effects

as their cytotoxic effects are unbiased, and in association

with neoplastic cells it can also affect normal tissues

(Hall, 2000; DeVita et al., 2004). In addition, the treat-

ment of cancer and its complications is very expensive,

and to patients in developing countries, where general

health care in itself is beyond the reach of most people,

the cost is exorbitant and unaffordable (Arora, 2010).

In the light of these observations, a large number of

patients, especially in the developing countries, prefer

complementary and alternative medicines for treating

and managing the symptoms of cancer and pain (Arora,

2010). Ayurveda, the traditional Indian system of medi-

cine, is one of the oldest systems of medicine and is

practised in the Indian subcontinent (Arora, 2010).

Emphasis in Ayurveda is on disease prevention and

promotion of good health by adopting a proper lifestyle

and following therapeutic measures, which will rejuve-

nate the body (Kulkarni, 1997). The Ayurvedic remedies,

which are both preventive and therapeutic, are mostly

made of plants and when compared with their synthetic

counterparts are either nontoxic or less toxic (Arora,

2010).

Some of the Ayurvedic formulations and plants used

in these preparations are globally receiving increasing

attention. In the recent past, these plants have been

Review article 225

0959-8278 �c 2011 Wolters Kluwer Health | Lippincott Williams & Wilkins DOI: 10.1097/CEJ.0b013e32834473f4

Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.

investigated for their pharmacological effects in accordance

with modern medicine (Arora, 2010). One such plant

that has been extensively studied is the medium-sized

deciduous tree Emblica officinalis Gaertn. or Phyllanthusemblica Linn belonging to the family Euphorbiaceae. The

plant species, which was originally native to India, is today

found growing in Pakistan, Uzbekistan, Sri Lanka, South-

East Asia, China, and Malaysia (Warrier et al., 1996; Zhang

et al., 2003; Khan, 2009). Colloquially, they are known as

Indian gooseberry tree, emblic myrobalans, and Malacca

tree in English and amla in Hindi. The other vernacular

names have been listed in Table 1.

All parts of the plant are of use in treating various ailments,

but the fruit, which is yellowish-green in color, globular in

shape, fleshy and smooth, striated with an obovate,

obtusely triangular six-celled nut, is of immense use in

various folk and traditional systems of medicine (Warrier

et al., 1996; Zhang et al., 2003; Khan, 2009) (Fig. 1). The

fruit is also of culinary use in making pickles, chutneys, and

vegetable dishes. Amla is also used to prepare a sweet

delicacy called murabbah, in which the ripe fruit is soaked

in concentrated sugar syrup for extended period till the

aroma of the fruits exudes into the sugar syrup. The ripe

fruit is also used to prepare fresh juice and has been

recently marketed as a concentrate to prepare readily

usable diluted juice (Warrier et al., 1996).

PhytochemistryAmla is one of the most extensively studied plants and

reports suggest that it contains tannins, alkaloids, and

phenolic compounds. Amla is a rich source of vitamin C

(478.56 mg/100 ml) and the levels are more than those in

oranges, tangerines, or lemons (Khan, 2009). The fruit also

contains gallic acid, ellagic acid, chebulinic acid, chebulagic

acid, emblicanin A, emblicanin B, punigluconin, peduncu-

lagin, citric acid, ellagotannin, trigallayl glucose, pectin, 1-O-

galloyl-b-D-glucose, 3,6-di-O-galloyl-D-glucose, chebulagic

acid, corilagin, 1,6-di-O-galloyl-b-D-glucose, 3 ethylgallic

acid (3 ethoxy 4,5 dihydroxy benzoic acid), and isostrictiniin

(Zhang et al., 2003). It also contains flavonoids such as

quercetin, kaempferol 3 O-a-L (600 methyl) rhamnopyrano-

side and kaempferol 3 O-a-L (600 ethyl) rhamnopyranoside

(Habib-ur-Rehman et al., 2007; Khan, 2009; Krishnaveni

and Mirunalini, 2010). Some of the phytochemicals are

shown in Fig. 2.

Traditional usesA number of medicinal properties are ascribed to amla

and it is a necessary constituent of many Ayurvedic

medicines (Warrier et al., 1996; Poltanov et al., 2009).

Various polyherbal formulations, such as Amlakadi gritha,

Amlakadi Tailya, Alakyadi churna, Aamalaki Rasayanam,

Asokarista, Avipatikara Churnam, Chyavananaprasa Leham,

Dasamularishta, Dhatri lauha, Dhatryarista, Kumaryasava,

Panchatika guggulu Ghritam, Thriphala Lepam, ThriphalaGuggulu, Thriphala Ghritam, and Thriphala Churnam, are

commonly used to treat various ailments (Warrier et al.,1996; Kulkarni, 1997).

It is also of use in Siddha, Unani Tibetan, Sri Lankan, and

Chinese systems of medicine (Warrier et al., 1996;

Poltanov et al., 2009). In Ayurveda, amla is considered to

be a potent rasayana (rejuvenator) and to be useful in

Table 1 Colloquial name of Phylanthus emblica in differentlanguages (Warrier et al., 1996; Pandey, 2002; Zhang et al., 2003;Habib-ur-Rehman et al., 2007; Khan, 2009; Poltanov et al., 2009;Krishnaveni and Mirunalini, 2010)

Language Names

Sanskrit Dhatriphala, Amla, Amaliki, Amalakan,Sriphalam, Vayastha, Amalaka, Dhatri

Hindi AmlaArabic Haliilaj or IhliilajChinese An moleEnglish Emblica myroblan, Indian gooseberryFrench Phyllanthe emblicaGerman AmlaItalian Mirabolano emblicoLao Mak kham bomMalaysian Popok melakaNepalese Amba, amalaPortuguese Mirabolano emblicoThai Ma kham pomTibetan Skyu-ru-raAssamese AmlakhiBengali AmlakiGujarati AmlaKannada NellikkaiKonkani AavaloMalayalam NellikkaManipuri HeikruMarathi Aavalaa, awlaOdiya AanlaPunjabi OlayTamil NellikkaiTelugu Usiri

Fig. 1

Photograph of amla.

226 European Journal of Cancer Prevention 2011, Vol 20 No 3


Fig. 2

HO

HO

HO

O

OO

OO

O

HO

HO

HOHO

HO

O

OO

O

O

O

O O

O

OO

OH

OH

Corilagin

Pedunculagin

OH

OH

OH

OH

OH

OH

HO

HO OHO OH

OH

OH

OH

OH

O

OH

(a) (b)

(c)

HO HO

HO

HO

HO

O

Gallic acid Ellagic acid

Pyrogallol

Quercetin Kaempferol

O

O

O

OOH

OH

OH

OH

OH

HOHO

O

O

O

OOH

OH

OH

OH

OH

OH

OH

OH

HO

HO

HOR

CO

HO

HO

HO

HO

OH

O

OO

O

OO

OO

OO

O

O

O OH

OH

OH

OHOH

O

HOHO

HO

HO

OH

H

O

O

O

O

COO

OOCO

OChebulic acid

Chebulinic acid

O OH

OH

OH

OH

OHR

COOCH2

HO

HO

HO

Some important phytochemicals of amla.

Amla (Emblica officinalis Gaertn) in cancer Baliga and Dsouza 227


stalling the degenerative and senescence process, to

promote longevity, enhance digestion, to treat constipa-

tion, reduce fever, purify the blood, reduce cough,

alleviate asthma, strengthen the heart, benefit the eyes,

stimulate hair growth, enliven the body, and enhance the

intellect (Pandey, 2002).

In various folk medicines the fruits, which are astringent,

are useful in treating ophthalmic problems, dyspepsia, gas-

tritis, hyperacidity, constipation, colitis, hemorrhoids,

hematuria, menorrhagia, treat anemia, diabetes, cough,

asthma, osteoporosis, premature graying of hair, weakness

and fatigue. Amla is also reported to possess hepatopro-

tective, cardioprotective, diuretic, laxative, refrigerant, sto-

machic, restorative, alterative, antipyretic, anti-inflammatory

properties, is a hair tonic, prevents peptic ulcer dyspepsia,

and is a digestive medicine (Pandey, 2002). It is used for

a variety of ailments such as anemia, hyperacidity,

diarrhea, eye inflammation, leucorrhea, jaundice, nerve

debility, liver complaints, cough, and anomalies of urine

(Pandey, 2002).

Scientifically validated studiesPreclinical studies carried out in the past three decades

have validated many of the traditional uses of amla.

Experiments have shown that amla possesses antibacte-

rial, antifungal, antiviral, antidiabetic, hypolipidemic,

antiulcerogenic, free radical scavenging, antioxidant, anti-

mutagenic, anti-inflammatory and immunomodulatory,

antipyretic, analgesic, antitussive, antiatherogenic, adap-

togenic, snake venom neutralizing, gastroprotective,

antianemia, antihypercholesterolemia, wound healing,

antidiarrheal, antiatherosclerotic, hepatoprotective, ne-

phroprotective, and neuroprotective properties (Khan,

2009; Krishnaveni and Mirunalini, 2010). Compelling

preclinical studies with both in-vitro and in-vivo systems

have shown that amla possesses anticancer, chemopreven-

tive, cytoprotective, and radioprotective effects. Here, an

attempt is made to analyze the role of amla in the

treatment and prevention of cancer.

Amla as an antineoplastic agentPreclinical studies have shown that the aqueous extract of

amla causes a concentration-dependent cytotoxic effect on

L 929 cells in vitro and that the IC50 was observed to be

16.5mg/ml (Jose et al., 2001). The extract also caused

apoptosis in Dalton’s lymphoma ascites and CeHa cell lines

(Rajeshkumar et al., 2003). Khan et al. (2002) studied the

antiproliferative activity of the extract in the human tumor

cell lines of different histological orgins (human erythro-

myeloid K562, B-lymphoid Raji, T-lymphoid Jurkat,

erythroleukemic HEL) and observed it to be effective.

Recently, Ngamkitidechakul et al. (2010) have observed

that the aqueous extract of amla, which contains tannins

(43%), uronic acid (11%), and gallic acid (21%), inhibited

the growth of A549 (lung), HepG2 (liver), HeLa (cervical),

MDA-MB-231 (breast), SK-OV3 (ovarian), and SW620

(colorectal) cells in vitro. However, at the same concentra-

tion the extract did not cause similar level of cytotoxicity

in the MRC5, normal lung fibroblast, suggesting it to be

safe for normal cells (Ngamkitidechakul et al., 2010). The

extract also induced apoptosis in HeLa, A549, MDA-MB-

231, and SK-OV3 cells (Ngamkitidechakul et al., 2010).

An amla extract possesses antiproliferative activity in

MCF7 and MDA-MB-231 breast cancer cell lines and

also induces an increase in ERamRNA in these cells

(Lambertini et al., 2004). The extract was devoid of

cytotoxic effects on the normal Chinese hamster ovary

cell line, suggesting it to be selectively cytotoxic to only

neoplastic cells (Sumantran et al., 2007). Administering

the extract to Dalton’s lymphoma-bearing mice caused a

reduction in ascitic volume (when the tumor cells were

inoculated in the peritoneum) and solid tumor growth

(when inoculated subcutaneously). The amla extract

significantly reduced the solid tumors and prolonged

survival time. At a molecular level, the extract was

observed to inhibit the cell cycle-regulating enzyme,

Cdc25 phosphatase, in a dose-dependent manner and the

IC50 was observed to be 5 mg/ml (Jose et al., 2001).

Studies have also shown that some of the compounds

present in amla are effective in inhibiting the prolifera-

tion of neoplastic cells in vitro and also in tumor-bearing

animals. The hydrolyzable tannins of amla are also re-

ported to possess selective cytotoxicity to the human oral

squamous cell carcinoma and salivary gland tumor cell

lines, while they were nontoxic to the normal human

gingival fibroblasts. The dimeric compounds, oenothein

B, woodfordin C, and woodfordin D, were more effective

than the monomeric compounds, while the macrocyclic

ellagitannin oligomers were more effective than gallic

acid and epigallocatechin gallate. These compounds also

induced apoptosis in the neoplastic cells and mechanistic

studies showed that the effect was mediated by the

prooxidant actions, but not through the generation of

hydrogen peroxide (Sakagami et al., 2000).

Zhang et al. (2004) evaluated the antiproliferative effects

of 18 phytochemicals of amla (norsesquiterpenoids,

phenolic compounds, and proanthocyanidin polymers)

in B16F10, HeLa, and MK-1 cells in vitro. Among the

norsesquiterpenoids, it was observed that the glycoside

phyllaemblicins B and C were highly potent in all the

three cells [B16F10 (GI50 at 2.0, 3.5 mg/ml, respectively),

HeLa (GI50 at 3.0, 12.0 mg/ml, respectively), and MK-1

(GI50 at 7.0 mg/ml for both compounds)]. However, with

respect to the phenolic compounds, all showed inhibi-

tory activity against the three tumor cell lines (at a

concentration of < 68 mg/ml), and were more effective

against B16F10 than against HeLa and MK-1 cells. The

highest activity was observed with corilagin, geraniin,

elaeocarpusin, and prodelphinidins B1 and B2 against

B16F10 (Zhang et al., 2004).



Pyrogallol, a catechin compound of amla, is also reported

to possess a potent antiproliferative effect on human lung

cancer cell lines and, to a lesser degree, on the human

bronchial epithelium cell line. Detailed studies with the

human lung cancer cell lines H441 (lung adenocarcino-

ma) and H520 (lung squamous cell carcinoma) have

shown that pyrogallol inhibited the growth of these cells,

triggered apoptosis by increasing Bax and concomitantly

decreasing Bcl-2, arrested the cells in the G2/M phase by

affecting the cyclin B1, Cdc25C and increasing the

phosphorylation of Cdc2 (Thr14). The in-vitro observa-

tions also extended into in-vivo studies with xenograft

nude mice (Yang et al., 2009).

Gallic acid, another chief constituent of amla, is also

shown to cause a concentration- and time-dependent

inhibition of proliferation, and to induce apoptosis in

BEL-7404 cells (Zhong et al., 2009). Gallic acid is also

shown to cause apoptosis in human non-small-cell lung

cancer NCI-H460 cells (Ji et al., 2009), A375.S2 human

melanoma cells (Ji et al., 2009), human bladder transi-

tional carcinoma cell line (TSGH-8301 cell) (Lo et al.,2010) and HeLa cervical cancer cells (You et al., 2010).

Consuming gallic acid (0.3–1% in drinking water)

inhibited the growth of prostate cancer and retarded

the progression to advanced-stage adenocarcinoma in

mice with transgenic adenocarcinoma of the prostate by

suppressing cell cycle progression and cell proliferation

and, concomitantly, increasing apoptosis (Raina et al.,2008). Gallic acid also suppressed lung xenograft tumor

growth (Ji et al., 2009). Some of the other phytochemicals

such as quercetin and kampferol also possess antineo-

plastic effects in the various cultured cell lines (Table 2)

and their presence may have also resulted in the observed

antineoplastic effect.

Chemomodulatory effectsChemotherapy is known to possess deleterious effects

on normal cells. At times, the effects can be extremely

severe and can compel the physician to discontinue or

reduce the dose of treatment. This will affect cancer

control and ultimately the survival of the patient. In

addition, the development of drug resistance is another

major problem in the treatment of cancer as chemoresis-

tance can lead to unabated proliferation of the defiant

tumor cells and the administered antineoplastic agent can

cause nonspecific toxicity to the normal cells. Accord-

ingly, an agent that can selectively protect the normal

cells against the deleterious effects of chemotherapy

(chemoprotective agents), or can sensitize the tumor

cells to anticancer drugs (chemosensetizers), is an

attractive proposition in cancer treatment and the goal

of researchers (Coleman et al., 1988).

The aqueous extract of amla has been observed to be

effective at reducing cyclophosphamide-induced suppres-

sion of humoral immunity and to restore the levels of

glutathione and the antioxidant enzymes in the kidneys

and liver of mice (Haque et al., 2001). Amla is reported

to decrease cyclophosphamide-induced DNA damage as

measured by a reduction in both micronuclei and chromo-

somal aberration in the bone marrow cells of mice (Sharma

et al., 2000a). Amla reduced the levels of cytochrome (Cyt)

P450, increased the levels of the antioxidant glutathione,

antioxidant enzymes [glutathione peroxidase (GPx), glu-

tathione reductase], and increased the detoxification

enzyme glutathione-S-transferase (GST), which thereby

contributed to these observations (Sharma et al., 2000a).

In-vitro studies have shown that amla effectively

suppressed the proliferation of the human hepatocellular

carcinoma (HepG2) and lung carcinoma (A549) cells and

Table 2 Phytochemicals of amla with reported antineoplasticactivities

Phytochemical Antineoplastic activity and the mechanism operating

Quercetin (1) Causes dose-dependent cell kill, chromatin condensation inthe colon cancer cells (Caco-2 and HT-29; Kuo, 1996)

(2) Potentiates inhibitory effect of a nontoxic dose of cisplatin,inhibits lung colonization of B16-BL6 colonies and in a dose-dependent manner (Caltagirone et al., 2000)

(3) Inhibits the growth of the highly aggressive PC-3 prostatecancer cell line and the moderately aggressive DU-145prostate cancer cell line, but ineffective on the poorlyaggressive LNCaP prostate cancer cell line or the normalfibroblast cell line BG-9 (Nair et al., 2004)

(4) Inhibits expression of specific oncogenes and genescontrolling G1, S, G2, and M phases of the cell cycle. It alsoupregulated the expression of several tumor suppressorgenes (Nair et al., 2004)

(5) Downregulates gelatinases A and B(matrixmetalloproteinases 2 and 9) in the human prostatecancer cells (PC-3) in vitro (Vijayababu et al., 2006)

Kaempferol (1) Inhibits proliferation and induces cell death in human gliomacells through caspase-dependent mechanisms involvingdownregulation of XIAP and survivin regulation by ERK andAkt (Jeong et al., 2009)

(2) Mediates p53-dependent growth inhibition and inducesapoptosis in human HCT116 colon cancer cell line byaffecting Bcl-2 family proteins, PUMA, and inducing ATM andH2AX phosphorylation (Li et al., 2009)

(3) Induces apoptosis in various oral cancer cell lines (SCC-1483, SCC-25, and SCC-QLL1) through the caspase-3-dependent pathway (Kang et al., 2010)

(4) Induces apoptosis through endoplasmic reticulum stressand mitochondria-dependent pathway in humanosteosarcoma U-2 OS cells (Huang et al., 2010)

Gallic acid (1) Induces apoptosis in human prostate LNCaP cells (Reddivariet al., 2010)

(2) Induces cytotoxic effects on DU145 prostate cancer cells,through generation of reactive oxygen species andmitochondria-mediated apoptosis (Chen et al., 2009)

(3) Blocks the growth of DU145 cells at G2/M phases byactivating chk1 and chk2 and inhibiting Cdc25C and Cdc2activities (Chen et al., 2009)

(4) Inactivates phosphorylation of Cdc25A/Cdc25C-Cdc2through ATM-chk2 activation, leading to cell cycle arrest, andinduces apoptosis in human prostate carcinoma DU145cells (Agarwal et al., 2006)

(5) Possess antiproliferative, proapoptotic, and antitumorigeniceffects against human prostate cells DU145 and 22Rv1in vitro and in nude mice (Kaur et al., 2009)

(6) Synergizes with doxorubicin to suppress the growth ofDU145 cells (Chen et al., 2009)

(7) Induces apoptosis through both caspase-dependent andcaspase-independent pathways in A375.S2 humanmelanoma cells (Lo et al., 2010)

(8) Possess in-vitro anticancer effects against human prostatecancer cells (Raina et al., 2008)



synergized the cytotoxic effects of doxorubicin and

cisplatin, two important clinically used antineoplastic

drugs (Pinmai et al., 2008). The ethanolic extract of amla

also protected the cardiac myoblasts H9c2 cells against

doxorubicin-induced toxicity (Wattanapitayakul et al.,2005). Together these observations suggest that it is

quite possible that amla prevents doxorubicin-induced

cardiotoxicity to the normal cardiac myoblasts and,

concomitantly, sensitizes the antineoplastic effects on

cancer cells. However, detailed studies are required for

this hypothesis to be validated, especially in the relevant

animal models of study.

Amla as a radioprotective agentSince the discovery of the deleterious effects of ionizing

radiation, studies have been focused on developing

chemical radioprotectors that have the ability to decrease

the ill effects of radiation on normal tissues (Arora et al.,2005). The thiol compound amifostine is credited with

being the only radioprotector to have been approved by

the Food and Drug Administration to reduce the

incidence and severity of xerostomia in head and neck

cancer patients undergoing radiotherapy (Arora et al.,2005). Unfortunately, the application of this drug has so

far been less than hoped for, owing to its untoward

toxicity often being evidenced at the optimal radio-

protective doses (Arora et al., 2005).

With regard to the radioprotective effects of amla, studies

have shown that administering (50, 100, 200, 400, and

800 mg/kg b.wt./day) amla once daily for 7 consecutive

days before exposure to sublethal dose of g-radiation

(9 Gy) protected mice against the radiation-induced

sickness and mortality (Singh et al., 2005). Among all

the doses studied, the optimal effect was observed at

100 mg/kg b.w. as it delayed the radiation-induced leth-

ality and caused a survival of 87.5% when compared with

placebo-treated irradiated cohorts in which no survivors

were observed (Singh et al., 2005).

Administration of amla (100 mg/kg b.wt.) ameliorated the

radiation (5 Gy)-induced gastrointestinal damage as

evaluated by the histopathological studies, by quantifying

the crypt cell population, mitotic figures, and villus

length at all the assay points (12 h–30 days). Reports also

suggest that amla ameliorated the radiation-induced

hemopoietic damage (Hari Kumar et al., 2004). Feeding

mice with 2.5 g/kg b.wt. of amla for 10 consecutive days

before exposure to a single dose of 7 Gy of radiation

increased the total leukocyte count, bone marrow viabi-

lity, and levels of hemoglobin. However, treatment with

amla after exposure to irradiation (continuously for an-

other 15 days) was not as effective when compared with

administeration before radiation, suggesting it to be of

use only when exposure to radiation is planned (Hari

Kumar et al., 2004).

Mechanistic studies have shown that feeding amla

enhanced the activity of the various antioxidant enzymes

(catalase, superoxide dismutase, and GPx), the phase II

detoxifying enzyme, GST, and the antioxidant thiol,

glutathione, in the blood, with a concomitant decrease in

the levels of lipid peroxides (Hari Kumar et al., 2004).

Similar results were also observed by Jindal et al. (2009) in

mice intestine and together both these studies confirm

that amla significantly reduces the deleterious effects of

radiation at least in part through its antioxidant and

inhibition of lipid peroxidation activities. The phyto-

chemicals ellagic acid, gallic acid, and quercetin (Fig. 2)

present in amla also possess radioprotective effects and

are shown in Table 3.

Amla as a chemopreventive agentCancer chemoprevention has traditionally been defined

as a dietary or therapeutic approach for the prevention,

delay, or reversal of carcinogenesis with nontoxic agents

(Bonte, 1993; Pastorino, 1994; Sporn and Suh, 2002).

Epidemiological studies have provided convincing evi-

dence that natural dietary compounds can modify the

process of carcinogenesis, which includes the three

decisive steps: namely initiation, promotion, and progres-

sion, in several types of human cancer (Sporn and Suh,

2002). Experimental studies have also validated the

efficacy of a number of bioactive dietary components,

supporting the acceptance of natural dietary compounds

as chemopreventive agents in the near future. Amla is

reported to be effective in stopping initiation, promotion,

and progression of cancer and the ability of amla to render

chemopreventive effects is discussed in the following

sections.

Table 3 Phytochemicals of amla with reported radioprotectiveactivities

Phytochemical Radioprotective effects and the mechanism operating

Gallic acid (1) Inhibits radiation-induced damage to the DNA and lipidperoxidation in both in-vitro and in-vivo conditions (Gandhiand Nair, 2005)

Ellagic acid (1) Protects yeast cells from g-radiation-induced damage byreducing DNA damage (Nemavarkar et al., 2004)

(2) Inhibits g-radiation-induced lipid peroxidation in aconcentration-dependent manner in vitro (Priyadarsini et al.,2002)

(3) Enhances the cytotoxic effects of radiation in neoplastic cells(Ehrlich ascites carcinoma and HeLa) by inducing freeradicals, reducing antioxidant enzymes, and altering themitochondrial potential, but protects the normal cells (spleniclymphocytes) of tumor-bearing mice against the radiationdamage (Bhosle et al., 2005)

Quercetin (1) Protected yeast cells from g-radiation damage by reducingDNA damage (Nemavarkar et al., 2004)

(2) Effective in protecting against g-radiation-induced DNAdamage to the human peripheral blood lymphocytes in vitro(Benkovic et al., 2008; Devipriya et al., 2008) and plasmidDNA (Devipriya et al., 2008). The protective mechanismswere mediated by the antioxidant action and inhibition of lipidperoxides (Devipriya et al., 2008)

(3) Intraperitoneal administration of quercetin 100 mg kg/kg for3 consecutive days before and/or after irradiation preventedradiation-induced DNA damage in white blood cells of mice.Pronounced effects were when querecetin was administeredbefore radiation (Benkovic et al., 2008; Benkovic et al.,2009)



Sancheti et al. (2005) investigated the chemopreventive

effects of amla in two-stage carcinogenesis {[7,12-

dimethylbenz(a)anthracene] (DMBA)-induced and croton

oil promoted} in mice by considering the delay in

tumorigenesis, cumulative number of papillomas, tumor

incidence, tumor yield, and tumor burden as the end

points. The researchers observed that feeding amla for

7 consecutive days before and after DMBA application was

less effective than when administered during the promo-

tion (starting from the time of croton oil treatment and

continued till the end of experiment for 16 weeks).

However, the best effect was observed when amla was fed

throughout the experimental period, that is, before and

after DMBA application and during the promotional stage.

These observations may be because of the various protective

mechanisms that were operating. When amla is administered

before DMBA treatment, there will be an increase in

the levels of antioxidant and phase II enzymes, with a

concomitant decrease in the phase I detoxifying enzymes,

which cumulatively may prevent/reduce the process of

carcinogenesis. However, when administered during the

promotion, amla may trigger the selective apoptosis of the

mutated and preneoplastic cells and decrease the carcino-

genesis (explained later). The phytochemicals, such as

ellagic acid, gallic acid, and quercetin, present in amla also

possess chemopreventive effects and may have been

responsible for the beneficial effects (Table 4).

Recently, Ngamkitidechakul et al. (2010) have also

observed that the aqueous extract of amla containing

tannins (43%), uronic acid (11%), and gallic acid (21%)

was effective in delaying and reducing DMBA-induced

and (12-otetradecanoylphorbol-13-acetate)-promoted skin

carcinogenesis in mice. The topical application of the

extract (1, 2, or 4 mg in 0.1 ml acetone) 1 h before each

(12-otetradecanoylphorbol-13-acetate) application until the

termination of the experiment caused a concentration-

dependent decrease in the appearance and incidence

of skin papillomas (Ngamkitidechakul et al., 2010). These

results clearly suggest the effectiveness of amla when

applied topically and also its possible use as a skin care

product.

In Ayurveda amla is considered to be a hepatoprotective

agent and scientific studies have validated this traditional

belief. Studies have shown that amla protects against

chemical-induced carcinogenesis and oxidative stress.

With regard to chemoprevention, studies by Rajeshkumar

et al. (2003) have shown that feeding amla decreased the

N-nitrosodiethylamine-induced liver tumors in rats. Amla

decreased the levels of serum g-glutamyl transpeptidase,

alkaline phosphatase, glutamate pyruvate transaminase,

and bilirubin (Rajeshkumar et al., 2003). Similar observa-

tions were also made when the chemopreventive effects

of amla were studied against diethylnitrosoamine-

induced and 2-acetylaminoflourine-promoted hepato-

carcinogenesis in rats (Sultana et al., 2008).

Table 4 Phytochemicals of amla with reported chemopreventiveeffects

Phytochemical Chemopreventive effects and the mechanism operating

Ellagic acid (1) Inhibitor of benzo[a]pyrene-induced pulmonary adenoma and7,12-dimethyl benz[a]anthracene-induced skin tumorigenesisin Swiss mice (Lesca, 1983)

(2) Topical application (Mukhtar et al., 1984a) and oral feeding ofellagic acid (Mukhtar et al., 1986) rendered protectionagainst 3-methylcholanthrene-induced skin tumorigenesis inmice and decreased tumor incidence, number of tumors,tumors per mouse, and tumors per tumor-bearing animal(Chang et al., 1985; Gali et al., 1992)

(3) Topical application of ellagic acid and oral before a tumor-initiation by B[a]P 7,8-diol-9,10-epoxide-2 and promotionwith 12-O-tetradecanoylphorbol-13-acetate reduced thenumber of skin tumors per mouse (Kaul and Khanduja, 1998)

(4) Ellagic acid applied topically to female CF-1 mice 20 minbefore each 12-O-tetradecanoylphorbol-13-acetatetreatment inhibited the induction of epidermal ornithinedecarboxylase activity, hydroperoxide production, and DNAsynthesis, and also inhibited the promotion of skin papillomasand carcinomas in the two-step initiation–promotion protocol(Del Tito et al., 1983)

(5) Topical application of ellagic acid simultaneously withphorbol-12-myristate-13-acetate or mezerein resulted insignificant protection against 7,12-dimethyl-benz[a]anthracene-induced skin tumors in mice (Makita et al.,1996)

(6) The levels of aryl hydrocarbon hydroxylase activity in skin andliver and the extent of 3H-BP-binding to skin, liver, and lungDNA were decreased (Mukhtar et al., 1984a)

(7) Is a potent inhibitor of benzo[a]pyrene metabolism and itssubsequent glucuronidation, sulfation, and covalent bindingto DNA in cultured BALB/C mouse keratinocytes. Carcino-genesis (Mukhtar et al., 1986)

(8) Inhibited the epidermal microsomal aryl hydrocarbonhydroxylase activity and benzo[a]pyrene (BP)-binding to bothcalf thymus DNA in vitro and to epidermal DNA in vivo (DelTito et al., 1983)

Gallic acid (1) Inhibits 12-O-tetradecanoylphorbol-13-acetate-inducedinduction of epidermal ornithine decarboxylase activity,hydroperoxide production, and DNA synthesis, and alsoinhibits the promotion of skin papillomas and carcinomas intwo-step initiation–promotion protocol (Gali et al., 1992)

(2) Administering gallic acid (0.3–1% gallic acid) for 20consecutive weeks from the age of 4 weeks to male TRAMPmice caused decreased tumors. Gallic acid brought aboutthis effect by decreasing the proliferative indexwith a concomitant increase in the apoptotic cells which wasdue to a decrease in the expression of Cdc2, CDK2, CDK4,CDK6, cyclin B1, and E which were also decreased by gallicacid feeding and increase in apoptosis (Raina et al., 2008)

Quercetin (1) Possesses chemopreventive effects against 4-nitroquinoline1-oxide-induction and its administration during eitherinitiation or postinitiation phases caused a significantreduction in the frequency of tongue carcinoma in rats. Itreduced the polyamine levels and the proliferation (Makitaet al., 1996)

(2) Prevents N-nitrosodiethylamine-induced lung tumorigenesisin mice (Khanduja et al., 1999)

(3) Prevents 20-methyl cholanthrene-induced cervical neoplasiain virgin Swiss albino mice by increasing the antioxidantenzymes, decreasing DNA damage and lipid peroxidation(De et al., 2000)

(4) Decreases 7,12-dimethyl benz[a]anthracene-induced DNAdamage (Sengupta et al., 2001)

(5) In a bioengineered human gingival epithelial tissue, quercetinwas observed to inhibit BaP-DNA binding, a precursor formutagenesis and carcinogenesis (Walle et al., 2006)

(6) Quercetin supplementation prevents benzo[a]pyrene-induced carcinogenesis by modulating the antioxidants anddecreasing lipid peroxidation, aryl hydrocarbon hydroxylase,g-glutamyl transpeptidase, 50-nucleotidase, lactatedehydrogenase, and adenosine deaminase (Kamaraj et al.,2007)

TRAMP, transgenic adenocarcinoma of the mouse prostate.



Prophylactic treatment with amla for 7 consecutive days

before the single administration of thioacetamide re-

verses the thioacetamide-induced oxidative stress and

early promotional events of primary hepato-carcinogen-

esis in rats. Amla inhibited the serum levels of SGOT,

SGPT, and GGT; decreased levels of lipid peroxide, in-

hibited aberrant synthesis of DNA; decreased the acti-

vities of GST, GR, G6PD, and ornithine decarboxylase;

and concomitantly increased the glutathione content and

GPx activity in the liver (Sultana et al., 2004).

Studies have also shown that administering amla reduces

the cytotoxic effects of the proven carcinogens such as

3,4-benzo(a)pyrene (Nandi et al., 1997), benzo[a]pyrene

(Sharma et al., 2000a), DMBA (Banu et al., 2004) by

reducing the mutagenesis, oxidative stress, lipid per-

oxides, phase I enzymes [cytochrome (Cyt) P450 and Cyt

b5], and concomitantly increasing the antioxidants

(glutathione) and enzymes (GPx, glutathione reductase,

and phase II detoxifying enzyme GST (Nandi et al., 1997;

Sharma et al., 2000a; Banu et al., 2004).

In addition to these observations, amla has been scienti-

fically studied for its protective role against country liquor

(Gulati et al., 1995), ethanol (Pramyothin et al., 2006; Reddy

et al., 2009), carbon tetrachloride (Sultana et al., 2005; Lee

et al., 2006; Mir et al., 2007), ochratoxin (Verma and

Chakraborty, 2008), hexachlorocyclohexane (Anilakumar

et al., 2007), paracetamol (Gulati et al., 1995), and the

antituberculosis drugs (rifampicin, isoniazid, and pyrazina-

mide) (Tasduq et al., 2005; Panchabhai et al., 2008)-induced

oxidative stress and damage to the liver. Most of these

agents are known to be hepatotoxins and to initiate and

promote carcinogenesis. By preventing oxidative stress and

the resulting damage, amla protects against both hepato-

toxicity and possible carcinogenesis.

Mechanisms of action (Fig. 3)Amla is a free radical scavenger

Excess generation of free radicals, the reactive oxygen

species [ROS superoxide anion radical (O2K – ), hydroxyl

radical (OHK) and hydrogen peroxide (H2O2)], and the

reactive nitrogen species [RNS nitric oxide (NO),

peroxynitrite (ONOO – )], respectively, causes oxidative

stress and nitrosative stress. The free radicals that are

generated are highly reactive and cause damage to the

membrane lipids, proteins, and DNA (Devasagayam et al.,2004). Accordingly, their prevention is important in

preventing cell damage, mutagenesis, and carcinogenesis.

In-vitro studies have shown that amla scavenges 2,2-

diphenyl-1-picrylhydrazyl radicals (Naik et al., 2005;

Hazra et al., 2010), superoxide anions (Naik et al., 2005;

Hazra et al., 2010), hydroxyl radical (Hazra et al., 2010),

nitric oxide (Hazra et al., 2010), hydrogen peroxide (Hazra

et al., 2010), peroxynitrite (Hazra et al., 2010), singlet

oxygen (Hazra et al., 2010), and hypochlorous acid (Hazra

et al., 2010). The phytochemicals, such as gallic acid,

ellagic acids, emblicanin A, and emblicanin B, are also

reported to possess free-radical-scavenging effects in the

2,2-diphenyl-1-picrylhydrazyl assay and efficacy was as

follows: A emblicanin greater than B emblicanin greater

than gallic acid greater than ellagic acid greater than

ascorbic acid (Pozharitskaya et al., 2007).

Studies have also shown that the methanol extract of

amla and its various fractions (hexane, ethyl acetate, and

water fractions) possess NO scavenging effects. The

isolated compounds, such as gallic acid, methyl gallate,

corilagin, furosin, and geraniin, which were isolated from

the ethyl acetate fraction that possessed the best NO-

scavenging effect, were also effective. Gallic acid was

found to be a major compound in the ethyl acetate

extract and geraniin showed highest NO-scavenging

activity among the isolated compounds (Kumaran and

Karunakaran, 2006).

Amla decreases phase I enzymes

Phase I drug-metabolizing enzymes, especially the CYP

P450 mixed-function oxidases, which are involved in the

biotransformation of xenobiotics, can transform a non-

toxic chemical (procarcinogen) into a harmful toxic subs-

tance (ultimate carcinogen), which can induce damage to

the nucleic acids and other macromolecules (Percival,

1997). Studies have also shown that administering the

ethanolic extract of amla reduced the hepatic levels of

the activating enzymes, Cyt P450 and Cyt b5, which are

important in converting the procarcinogen DMBA into

ultimate carcinogen (Banu et al., 2004). In addition, the

inhibition of microsomal-activating enzymes, including

Cyt P450, was also responsible for the antimutagenic

effects of amla against 2-aminofluorene (Arora et al.,2003), aflatoxin B1, and benzo[a]pyrene-induced muta-

genesis in the Ames test (Sharma et al., 2000b).

Amla increases glutathione S-transferase, a phase II

enzyme

The reactive species formed by the phase I enzymes are

often detoxified by phase II drug-metabolizing enzymes.

In the reaction, the hydrophobic intermediates generated

by the phase I enzymes are converted to a water-soluble

group, thus decreasing their reactive nature, and allowing

subsequent excretion (Jana and Mandlekar, 2009).

A properly functioning and balanced phase II system

would detoxify the metabolically activated carcinogen,

thereby preventing mutagenesis and carcinogenesis.

Agents preferentially activating phase II over phase I

enzymes can be more beneficial as chemopreventive

agents (Percival, 1997; Jana and Mandlekar, 2009).

Studies have shown that amla increases the level of GST

and thereby reduces the toxic effects of N-nitrosodiethy-

lamine (Jeena et al., 1999; Rajeshkumar et al., 2003),

benzo[a]pyrene (Sharma et al., 2000a), cyclophosphamide

(Sharma et al., 2000a), thioacetamide (Sultana et al.,2004), CCl4 (Sultana et al., 2005), ionizing radiation (Hari



Kumar et al., 2004), hexachlorocyclohexane (Anilakumar

et al., 2007), arsenic (Panchabhai et al., 2008), ethanol

(Reddy et al., 2009), and ochratoxin (Sultana et al., 2004).

Molecular studies have also shown that amla increased

GSTP1 expression (Niture et al., 2006), thereby valida-

ting the biochemical observation.

Amla decreases ornithine decarboxylase

Ornithine decarboxylase (ODC), the rate-limiting en-

zyme in polyamine synthesis, is important in polyamine

synthesis. High levels of ODC are an adverse prognostic

factor as it is observed to be important in tumor proli-

feration, progression, and metastasis and for the survival

of cancer patients (Manni et al., 2002).

Studies have shown that administering amla inhibited

thioacetamide-induced hyper-proliferation in rat liver

by decreasing the levels of ODC activity and thymidine

incorporation in DNA (Sultana et al., 2004). These obser-

vations clearly indicate the inhibitory effects of amla on

ODC and DNA replication, steps that are important in

tumor cell proliferation.

Amla increases the antioxidant enzymes

The antioxidant enzymes, superoxide dismutase, GPx,

and catalase, cooperate or, in a synergistic method, work

to protect cells against oxidative stress. The superoxide

dismutase catalyses the dismutation of superoxide

radicals, a major form of ROS, into hydrogen peroxide,

which is acted on by the GPx and catalase to give water.

When an appropriate balance exists between these three

enzymes, oxidative stress is reduced and the cells are

protected from the cytotoxic and mutagenic effects of the

ROS (Devasagayam et al., 2004).

Preclinical studies have conclusively shown that amla

ameliorates the oxidative and xenobiotic-induced stress,

mutagenesis, and carcinogenesis by increasing the anti-

oxidant enzymes. Reports suggest that amla increases

the antioxidant enzymes and prevents benzo[a]pyrene

(Sharma et al., 2000a), cyclophosphamide (Sharma et al.,2000a), DMBA (Banu et al., 2004), g-radiation (Hari Kumar

et al., 2004; Jindal et al., 2009), hexachlorocyclohexane

(Anilakumar et al., 2007), and ethanol (Pramyothin et al.,2006)-induced toxic effects.

Amla decreases lipid peroxidation

Lipid peroxidation is one of the most evaluated con-

sequences of free radicals on membrane structure. The

polyunsaturated fatty acids are vulnerable to peroxidative

attack and this can cause loss of fluidity, decreased

membrane potential, increased permeability for protons

and calcium ions and eventually loss of cell membranes,

and result in pathological and toxicological processes

(Devasagayam et al., 2004). The major aldehydic end

Fig. 3

Immune modulation

DNA damage

Mutagenesis

Ornithine decarboxylase

Phase II detoxificationenzymes

Phase I detoxificationenzymes

Antioxidant enzymes

Glutathione

Amla Inflammation

Oxidative stress

Lipid peroxidation

Free radical scavenging

Some of the protective mechanisms responsible for the radioprotective and chemoprotective effects of amla (arrow pointing up depicts increase,whereas down signifies decrease).



product of lipid peroxidation is malondialdehyde and is

mutagenic in the bacterial and mammalian systems of

studies.

Multiple studies have shown that amla possesses inhibitory

effects on lipid peroxidation induced by various inducers.

In-vitro studies have shown that amla prevents radiation-

induced lipid peroxidation (Naik et al., 2005) and this effect

also extends to animal studies (Hari Kumar et al., 2004;

Jindal et al., 2009). Amla inhibits cadmium (Khandelwal

et al., 2002), carbon tetra chloride (Sultana et al., 2005),

arsenic (Panchabhai et al., 2008), ethanol (Reddy et al.,2009), ochratoxin (Chakraborty and Verma, 2010), N-

nitrosodiethylamine (Rajeshkumar et al., 2003), and thioa-

cetamide (Anilakumar et al., 2007)-induced lipid peroxida-

tion. By inhibiting lipid peroxidation amla may contribute

toward the observed beneficial effects, at least in part.

Amla possess anti-inflammatory effects

Chronic inflammation has been proved to cause free

radicals and the resulting oxidative and nitrosative stress

is known to directly or indirectly contribute toward mali-

gnant cell transformation by inducing genomic instabi-

lity, alterations in epigenetic events, inappropriate gene

expression, enhanced proliferation of mutated cells, resis-

tance to apoptosis, tumor neovascularization, and meta-

stasis (Kundu and Surh, 2005).

Experiments have shown that the aqueous fraction of

methanol extract of the leaves possesses anti-inflammatory

effects in carrageenan-induced and dextran-induced rat

hind paw edema. Mechanistically, it was observed that the

extract inhibited migration of human polymorphonuclear

cells and exerted its anti-inflammatory effects (Asmawi

et al., 1993). Studies have also shown that amla extract and

the phytochemical pyrogallol also possess anti-inflamma-

tory effects and inhibited the Pseudomonas aeruginosa labora-

tory strain PAO1-dependent expression of the neutrophil

chemokines IL-8, GRO-a, GRO-g, of the adhesion

molecule, ICAM-1, and of the pro-inflammatory cytokine,

IL-6 (Nicolis et al., 2008). Recently, Muthuraman et al.(2010) have also observed that the phenolic compounds

from amla possess anti-inflammatory effects in the

carrageenan and cotton pellet-induced acute and chronic

inflammatory response in animal models of study. The

effect was significant at high doses and was comparable to

the positive control, diclofenac (Muthuraman et al., 2010).

Antimutagenic effects

The initial step in the process of carcinogenesis is induc-

tion of mutation in the oncogenes or tumor-suppressor

genes of the genome of a somatic cell. Therefore, its

prevention is of great importance (Weisburger, 2001).

Multiple studies carried out in the last two decades have

conclusively shown that amla prevents DNA damage

against different carcinogens and mutagens. Using the

standard Ames test, Sharma et al. (2000b) observed for

the first time that the aqueous extract of amla inhibited

aflatoxin B1 and benzo[a]pyrene-induced mutagenesis in

the Salmonella typhimurium strains TA 98 and TA 100.

Amla is also reported to increase the levels and activities

of O6-methylguanine-DNA methyltransferase, an en-

zyme important for removing the highly mutagenic

adducts formed by alkylating agents in human lympho-

cytes (Niture et al., 2006). Amla was also effective in

preventing the radiation-induced damage in the plasmid

DNA assay (Naik et al., 2005), suggesting its effectiveness

against different classes of mutagens.

In addition, studies with experimental animals have shown

that amla prevents cadmium (Khandelwal et al., 2002), lead

(Dhir et al., 1990), aluminium (Dhir et al., 1990), nickel

(Dhir et al., 1991), cesium chloride (Ghosh et al., 1992),

arsenic (Biswas et al., 1999), chromium (Sai Ram et al.,2003), 3,4-benzo(a)pyrene (Nandi et al., 1997), benzo[a]-

pyrene (Sharma et al., 2000a), DMBA (Nandi et al., 1997),

and cyclophosphamide (Sharma et al., 2000a)-induced

DNA damage. Together these observations clearly suggest

the effectiveness of amla in preventing mutagenesis and

DNA damage, which would inhibit/reduce the incidence

and process of carcinogenesis, at least in part.

Amla possesses immunomodulatory effects

Immune activation is an effective protective approach

against emerging infectious diseases and certain cancers.

Immunostimulants enhance the overall immunity of the

host, present a nonspecific immune response against

microbial pathogens and increase humoral and cellular

immune responses, by either enhancing cytokine secretion,

or by directly stimulating B-lymphocytes or T-lymphocytes

(Spelman et al., 2006). In Ayurveda, amla is considered to

be an immunostimulatory agent and scientific studies have

validated this (Warrier et al., 1996; Kulkarni, 1997; Khan,

2009; Krishnaveni and Mirunalini, 2010).

Studies have shown that amla enhances natural killer

(NK) cell activity and antibody-dependent cellular

cytotoxicity in BALB/c mice bearing Dalton’s lymphoma

ascites tumor. Amla increases the life span of tumor-

bearing animals and this was because of the increase in

the activation of splenic NK cell activity and antibody

dependent cellular cytotoxicity. However, the increase in

survival was completely abrogated when the NK cell and

killer cell activities were depleted, either by cyclopho-

sphamide or anti-asialo-GM1 antibody treatment, validat-

ing that the observed effects were because of its immuno-

modulatory effects (Suresh and Vasudevan, 1994).

Amla and its phytochemicals modulate the levels

of proteins important in cell cycle progression

Cancer is frequently considered to be a disease of the cell

cycle and a convincing body of data has proved that the

disruption of the normal regulation of cell-cycle progres-

sion and division are important events in cancer deve-

lopment (Hanahan and Weinberg, 2000; Kastan and



Bartek, 2004). The progression of the cell cycle is a

tightly regulated and highly ordered process involving

multiple checkpoints that assess extracellular growth

signals, cell size, and DNA integrity (Kastan and Bartek,

2004). The cyclin-dependent kinases (CDKs) and their

respective partners (cyclin) are responsible for the

progression of the cell cycle, whereas the CDK inhibitors

act as brakes to stop cell cycle progression (Hartwell and

Weinert, 1989). The genesis of cancer is principally because

of the derailed expression or activation of positive

regulators and functional suppression of negative regulators

(Hartwell and Weinert, 1989; Kastan and Bartek, 2004).

Studies by Jose et al. (2001) have shown for the first time

that amla extract caused a dose-dependent inhibition of

the cell cycle-regulating enzyme Cdc25 phosphatase

in vitro, with an IC50 of 5 mg/ml (Jose et al., 2001). The

phytochemical pentagalloylglucose is shown to cause G1

arrest in human Jurkat T cells by elevating p27Kip1 and

p21Cip1/WAF1 proteins (Chen and Lin, 2004). Gallic

acid induces cell cycle arrest by decreasing CDKs and

cyclins. It phosporylates Cip1/p21 and cell division cycle

2 (Cdc2), Cdc25A, and Cdc25C in DU145 cells (Sun

et al., 2004). It also induces G2/M phase cell cycle arrest

by regulating 14-3-3b release from Cdc25C; activation of

chk2; decreasing CDK1, cyclin B1, and Cdc25C; increas-

ing phosphorylation of p-Cdc2 (Tyr-15), Cip1/p21 and

Cdc25C in human bladder transitional carcinoma cells

(TSGH-8301cells) (Ou et al., 2010). Gallic acid feeding

also reduces Cdc2, CDK2, CDK4, CDK6, cyclin B1, and E

in the prostatic tissue of mice with transgenic adenocarci-

noma of the mouse prostate (Raina et al., 2008).

Amla and some of its constituents cause apoptosis

and cytotoxicity of neoplastic cells

Apoptosis, a process by which the cell is committed to

death by not initiating an inflammatory response, is

vital in regulating tissue homeostasis (Sun et al., 2004;

Ghobrial et al., 2005). A large body of evidence has proved

that the processes of neoplastic transformation, progres-

sion, and metastasis involve alterations of the normal

apoptotic pathway and that the number of cell deaths is

very low in these cells (Sun et al., 2004; Ghobrial et al.,2005). Therefore, the induction of apoptosis is arguably

the most potent defence against cancer as it effectively

eliminates the mutated and severely damaged cells.

Accordingly, agents that can eliminate mutated, preneo-

plastic, and neoplastic cells by sparing the normal cells

are supposed to be an effective chemopreventive agent

and to offer therapeutic advantage in the elimination of

cancer cells (Sun et al., 2004; Ghobrial et al., 2005).

The ability of the extract of amla and some of its

phytochemicals to induce apoptosis in cancer cells con-

tributes to the understanding of its anticancer and

chemopreventive potential. Studies have shown that

the aqueous extract of amla induces apoptosis and

inhibits the growth of HeLa, MDA-MB-231, and SK-

OV3 without affecting the normal lung fibroblast, MRC5

(Ngamkitidechakul et al., 2010). The hydrolyzable tannins

possess selective cytotoxicity to the human oral squamous

cell carcinoma and salivary gland tumor cell lines, whereas

they were nontoxic to the normal human gingival fibro-

blasts (Sakagami et al., 2000). Studies have also shown that

quercetin (Son et al., 2004), gallic acid (Isuzugawa et al.,2001), ellagic acid (Losso et al., 2004), and pyrogallol (Yang

et al., 2009) also possess cytotoxic and apoptogenic effects

on the neoplastic and transformed cells, but not in normal

cells. Together, these observations clearly suggest that the

presence of these compounds in amla resulted in the eli-

mination of the mutated and neoplastic cells and resulted

in the desired effects in both antineoplastic effects and

chemoprevention.

Amla and some of its constituents prevent

metastasis

Cancer cells differ from normal cells; the most important

being the loss of differentiation, self-sufficiency in growth

signals, limitless replicative potential, decreased drug

sensitivity, increased invasiveness, and metastasis (Hanahan

and Weinberg, 2000). Metastasis, the process by which

some of the neoplastic cells spread from the primary site

to distant tissue, is the life-threatening aspect of cancer.

It is the hallmark of cancer and is responsible for the

failure of treatment and death. The process of tumor

metastasis is extremely complex and involves myriad bio-

chemical interactions operating concurrently or sequen-

tially. The important steps in the process of metastasis

are (i) invasion and migration, (ii) intravasation, (iii)

circulation, (iv) extravasation, and (v) colonization,

proliferation, and angiogenesis (Chiang and Massague,

2008; Leber and Efferth, 2009). Cell invasion is one of

the fundamental processes required during tumor pro-

gression and metastasis and matrix metalloproteinases

(MMPs), a group of enzymes that regulate cell-matrix

composition, are important in this process (Chiang and

Massague, 2008; Leber and Efferth, 2009).

Recent studies have suggested that the aqueous extract

of amla was effective in preventing the invasion of MDA-

MB-231 cells in the in-vitro matrigel invasion assay

(Ngamkitidechakul et al., 2010). The amla phytochem-

ical, kaempferol, inhibited the expression of stromelysin 1

(MMP-3) in the MDA-MB-231 breast cancer cell line

(Phromnoi et al., 2009). The polyphenol gallic acid is also

reported to possess inhibitory effects on gastric adeno-

carcinoma cell migration, decreased expression of MMP-

2/9 in vitro (Ho et al., 2010), and metastasis of P815

mastocytoma cells to the liver of DBA/2 mice (Ohno et al.,2001). The flavanol, quercetin, decreased the expression

of gelatinases A and B (MMP-2 and MMP-9) in the

human metastatic prostate PC-3 cells (Vijayababu et al.,2006) and stromelysin 1 (MMP-3) in the MDA-MB-231

breast cancer cell line (Phromnoi et al., 2009) and



inhibited the lung metastasis of murine colon 26-L5 car-

cinoma cells (Ogasawara et al., 2007) and B16-BL6 murine

melanoma metastasis in mice (Piantelli et al., 2006).

Conclusion

Preclinical studies carried out in the past two decades

have clearly shown that amla possesses antineoplastic,

chemomodulatory, chemopreventive, and radioprotective

effects. Several mechanisms are likely to be responsible

for the observed effects, the most important being the

induction of apoptosis of neoplastic and preneoplastic

cells, free radical scavenging, antioxidant, antimutagenic,

anti-inflammatory activities; increase in the antioxidant

enzymes, modulation of phase I and II enzymes and

immunomodulatory effects (Fig. 3). It is unlikely that all

targets and cell biological effects found in vitro individu-

ally may be operating in the animal system, but studies

should be attempted to understand whether the effects

observed in vitro translate to the animal system.

Although studies on the effects of amla on some cancer

cell lines and animals substantiate its effectiveness,

countless possibilities for investigation still remain.

Relevant animal and cell culture studies are required to

understand the underlying mechanism of action, espe-

cially with the phytochemicals. In addition, rationally

designed clinical trials are also needed to understand the

maximum permissible dose and also to assess for its

adverse effects, if any, following consumption over longer

periods.

From a phytochemical perspective, there is considerable

variation in the composition among various samples of

amla. A quality control should be established for the

authenticity of the plant and the presence of active

phytochemicals, especially gallic acid, ellagic acid, chebu-

linic acid, quercetin, chebulagic acid, corilagin, kaempferol,

apigenin, luteolin, emblicanin A, and emblicanin B in the

required levels. Experiments should also be performed to

understand which of the phytochemicals are effective and

their mechanisms of action.

Studies indicate that amla and some of its phytochem-

icals (gallic acid, pentagalloylglucose, ellagic acid, quer-

cetin, and kaempferol) are cytotoxic to neoplastic cells,

whereas the normal cells are unaffected. It is quite

possible that these compounds exert their effects on

neoplastic cells that have aberrant cell cycle progression.

It is observed that these molecules induce apoptosis and

cytotoxicity by modulating the proteins involved in cell

progression, and the observations of Jose et al. (2001)

support the hypothesis. However, detailed studies are

needed on this aspect with a range of cells encompass-

ing normal, mutated, preneoplastic, and highly metastatic

cell lines of different histological origins and cell doubling

time.

Owing to its abundance, low cost, and safety in

consumption, amla remains a species with tremendous

potential and countless possibilities for further investiga-

tion. Amla has the potential to develop as a nontoxic

anticancer, chemopreventive agent, and as an adjuvant to

radiotherapy and chemotherapy when lacunas existing in

knowledge are understood. The outcomes of such studies

may be useful for the clinical applications of amla in

humans against different cancers and may open up a new

therapeutic avenue.

AcknowledgementsThe authors are grateful to Rev. Fr. Patrick Rodrigus

(Director), Rev. Fr. Denis D’Sa (Administrator), Dr

Sanjeev Rai (Chief of Medical Services), and Dr Jaya

Prakash Alva, (Dean) of Father Muller Medical College

for their unstinted support. They also thank to Harshith

P. Bhat for drawing the chemical structures. The authors

dedicate this review to Professor Ramdasan Kuttan of

Amala Cancer Centre, Thrissur, India. Professor Kuttan is

a pioneer cancer researcher and his work on the radio-

protective and chemopreventive effects with amla has

been a source of inspiration to the authors. This study

was not supported by any private or public funding body.

The authors declare that they do not have any conflict of

interest.

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Emblica officinalis Gaertn), a wonder berry in the