Amla (Emblica Officinalis Gaertn), a Wonder Berry in the Treatment and Prevention of Cancer Manjeshwar Shrinath Baliga and Jason Jerome Dsouza

Review article 225

Amla (Emblica officinalis Gaertn), a wonder berry in the treatment and prevention of cancer Manjeshwar Shrinath Baliga and Jason Jerome Dsouza

Emblica officinalis Gaertn. or Phyllanthus emblica Linn, chemomodulatory, chemopreventive effects, free radical commonly known as Indian gooseberry or amla, is arguably scavenging, antioxidant, anti-inflammatory, antimutagenic the most important medicinal plant in the Indian traditional and immunomodulatory activities, properties that are system of medicine, the Ayurveda. Various parts of the efficacious in the treatment and prevention of cancer. This plant are used to treat a range of diseases, but the most review for the first time summarizes the results related to important is the fruit. The fruit is used either alone or in these properties and also emphasizes the aspects that combination with other plants to treat many ailments such warrant future research to establish its activity and as common cold and fever; as a diuretic, laxative, liver tonic, utility as a cancer preventive and therapeutic drug in refrigerant, stomachic, restorative, alterative, antipyretic, humans. European Journal of Cancer Prevention anti-inflammatory, hair tonic; to prevent peptic ulcer and 20:225–239 c 2011 Wolters Kluwer Health | Lippincott dyspepsia, and as a digestive. Preclinical studies have Williams & Wilkins. shown that amla possesses antipyretic, analgesic, European Journal of Cancer Prevention 2011, 20:225–239 antitussive, antiatherogenic, adaptogenic, cardioprotective, gastroprotective, antianemia, antihypercholesterolemia, Keywords: amla, anticancer, chemomodulation, chemoprevention, Emblica officinalis, Phyllanthus emblica, radiation protection wound healing, antidiarrheal, antiatherosclerotic, hepatoprotective, nephroprotective, and neuroprotective Father Muller Medical College, Kankanady, Mangalore, Karnataka, India properties. In addition, experimental studies have shown Correspondence to Manjeshwar Shrinath Baliga, PhD, Research and that amla and some of its phytochemicals Development, Father Muller Medical College, Father Muller Hospital Road, Kankanady, Mangalore, Karnataka 575003, India such as gallic acid, ellagic acid, pyrogallol, some Tel: + 91 824 2238331; fax: + 91 824 2437402/2436352; norsesquiterpenoids, corilagin, geraniin, elaeocarpusin, e-mail: [email protected] and prodelphinidins B1 and B2 also possess antineoplastic Received 6 September 2010 Accepted 14 December 2010 effects. Amla is also reported to possess radiomodulatory,

Introduction (Hall, 2000; DeVita et al., 2004). In addition, the treat- Despite all the advances in medical sciences, cancer, a ment of cancer and its complications is very expensive, disease as old as humankind, is globally a major health and to patients in developing countries, where general problem (Arora, 2010). Recent reports from the Interna- health care in itself is beyond the reach of most people, tional Agency for Cancer Research indicate that in 2008, the cost is exorbitant and unaffordable (Arora, 2010). approximately 12.7 million new cancer cases and 7.6 million cancer deaths occurred and of these, 56% of all In the light of these observations, a large number of new cancer cases and 63% of cancer deaths were in the patients, especially in the developing countries, prefer less developed regions of the world (Ferlay et al., 2010). complementary and alternative medicines for treating Projections are that by 2020, the incidence of cancer will and managing the symptoms of cancer and pain (Arora, increase three-fold, and that there will be a dispropor- 2010). Ayurveda, the traditional Indian system of medi- tionate rise in cancer cases and deaths from the develop- cine, is one of the oldest systems of medicine and is ing countries that have limited resources to tackle the practised in the Indian subcontinent (Arora, 2010). problem (Are et al., 2010). Emphasis in Ayurveda is on disease prevention and promotion of good health by adopting a proper lifestyle Conventionally, when localized, cancer may be treated and following therapeutic measures, which will rejuve- with either surgery (if operable), or with ionizing radia- nate the body (Kulkarni, 1997). The Ayurvedic remedies, tion (when inoperable), or by combining both these which are both preventive and therapeutic, are mostly modalities. However, in the advanced stage, and more made of plants and when compared with their synthetic importantly, when metastasis is observed, the use of cyto- counterparts are either nontoxic or less toxic (Arora, toxic chemotherapeutic agents is obligatory (DeVita et al., 2010). 2004). Unfortunately, the use of chemotherapy and ionizing radiation is associated with deleterious side effects Some of the Ayurvedic formulations and plants used as their cytotoxic effects are unbiased, and in association in these preparations are globally receiving increasing with neoplastic cells it can also affect normal tissues attention. In the recent past, these plants have been

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

investigated for their pharmacological effects in accordance Fig. 1 with modern medicine (Arora, 2010). One such plant that has been extensively studied is the medium-sized deciduous tree Emblica officinalis Gaertn. or Phyllanthus emblica 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 Photograph of amla. 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). (478.56 mg/100 ml) and the levels are more than those in oranges, tangerines, or lemons (Khan, 2009). The fruit also Phytochemistry contains gallic acid, ellagic acid, chebulinic acid, chebulagic Amla is one of the most extensively studied plants and acid, emblicanin A, emblicanin B, punigluconin, peduncu- reports suggest that it contains tannins, alkaloids, and lagin, citric acid, ellagotannin, trigallayl glucose, pectin, 1-O- phenolic compounds. Amla is a rich source of vitamin C galloyl-b-D-glucose, 3,6-di-O-galloyl-D-glucose, chebulagic acid, corilagin, 1,6-di-O-galloyl-b-D-glucose, 3 ethylgallic Table 1 Colloquial name of Phylanthus emblica in different acid (3 ethoxy 4,5 dihydroxy benzoic acid), and isostrictiniin languages (Warrier et al., 1996; Pandey, 2002; Zhang et al., 2003; (Zhang et al., 2003). It also contains flavonoids such as Habib-ur-Rehman et al., 2007; Khan, 2009; Poltanov et al., 2009; 00 Krishnaveni and Mirunalini, 2010) quercetin, kaempferol 3 O-a-L (6 methyl) rhamnopyranoside and kaempferol 3 O-a-L (600 ethyl) rhamnopyranoside Language Names (Habib-ur-Rehman et al., 2007; Khan, 2009; Krishnaveni Sanskrit Dhatriphala, Amla, Amaliki, Amalakan, and Mirunalini, 2010). Some of the phytochemicals are Sriphalam, Vayastha, Amalaka, Dhatri Hindi Amla showninFig.2. Arabic Haliilaj or Ihliilaj Chinese An mole English Emblica myroblan, Indian gooseberry Traditional uses French Phyllanthe emblica German Amla A number of medicinal properties are ascribed to amla Italian Mirabolano emblico and it is a necessary constituent of many Ayurvedic Lao Mak kham bom medicines (Warrier et al., 1996; Poltanov et al., 2009). Malaysian Popok melaka Nepalese Amba, amala Various polyherbal formulations, such as Amlakadi gritha, Portuguese Mirabolano emblico Amlakadi Tailya, Alakyadi churna, Aamalaki Rasayanam, Thai Ma kham pom Asokarista, Avipatikara Churnam, Chyavananaprasa Leham, Tibetan Skyu-ru-ra Assamese Amlakhi Dasamularishta, Dhatri lauha, Dhatryarista, Kumaryasava, Bengali Amlaki Panchatika guggulu Ghritam, Thriphala Lepam, Thriphala Gujarati Amla Kannada Nellikkai Guggulu, Thriphala Ghritam, and Thriphala Churnam, are Konkani Aavalo commonly used to treat various ailments (Warrier et al., Malayalam Nellikka 1996; Kulkarni, 1997). Manipuri Heikru Marathi Aavalaa, awla It is also of use in Siddha, Unani Tibetan, Sri Lankan, and Odiya Aanla Punjabi Olay Chinese systems of medicine (Warrier et al., 1996; Tamil Nellikkai Poltanov et al., 2009). In Ayurveda, amla is considered to Telugu Usiri be a potent rasayana (rejuvenator) and to be useful in

Fig. 2

HO (a)OH (b) O HO COOCH2 HO OH HO O OH HO HO R R OOC HO OH O OH HO CO O OH O O HO O HO COO OH H O HO O O OH HO Gallic acid Ellagic acid O OH OH O Chebulic acid HO OH OH HO

HO O Pyrogallol OH OH OH O OH O O OH HO O OH O O O HO HO O HO O O OH O O O OH OH OH HO HO O OH Quercetin Kaempferol OH O OH O O Chebulinic acid (c) OH

HO O O HO OH O HO O O O OH

HO OH O OH OH OH OH Corilagin HO O

HO OH HO O O OH O O O O O HO O OH OH O O

HO OH

HO OHO OH Pedunculagin

Some important phytochemicals of amla.

stalling the degenerative and senescence process, to (colorectal) cells in vitro. However, at the same concentra- promote longevity, enhance digestion, to treat constipation the extract did not cause similar level of cytotoxicity tion, reduce fever, purify the blood, reduce cough, in the MRC5, normal lung fibroblast, suggesting it to be alleviate asthma, strengthen the heart, benefit the eyes, safe for normal cells (Ngamkitidechakul et al.,2010).The stimulate hair growth, enliven the body, and enhance the extract also induced apoptosis in HeLa, A549, MDA-MB- intellect (Pandey, 2002). 231, and SK-OV3 cells (Ngamkitidechakul et al., 2010). In various folk medicines the fruits, which are astringent, An amla extract possesses antiproliferative activity in are useful in treating ophthalmic problems, dyspepsia, gas- MCF7 and MDA-MB-231 breast cancer cell lines and tritis, hyperacidity, constipation, colitis, hemorrhoids, also induces an increase in ERamRNA in these cells hematuria, menorrhagia, treat anemia, diabetes, cough, (Lambertini et al., 2004). The extract was devoid of asthma, osteoporosis, premature graying of hair, weakness cytotoxic effects on the normal Chinese hamster ovary and fatigue. Amla is also reported to possess hepatopro- cell line, suggesting it to be selectively cytotoxic to only tective, cardioprotective, diuretic, laxative, refrigerant, sto- neoplastic cells (Sumantran et al., 2007). Administering machic, restorative, alterative, antipyretic, anti-inflammatory the extract to Dalton’s lymphoma-bearing mice caused a properties, is a hair tonic, prevents peptic ulcer dyspepsia, reduction in ascitic volume (when the tumor cells were and is a digestive medicine (Pandey, 2002). It is used for inoculated in the peritoneum) and solid tumor growth a variety of ailments such as anemia, hyperacidity, (when inoculated subcutaneously). The amla extract diarrhea, eye inflammation, leucorrhea, jaundice, nerve significantly reduced the solid tumors and prolonged debility, liver complaints, cough, and anomalies of urine survival time. At a molecular level, the extract was (Pandey, 2002). observed to inhibit the cell cycle-regulating enzyme, Cdc25 phosphatase, in a dose-dependent manner and the Scientifically validated studies IC was observed to be 5 mg/ml (Jose et al., 2001). Preclinical studies carried out in the past three decades 50 have validated many of the traditional uses of amla. Studies have also shown that some of the compounds Experiments have shown that amla possesses antibacte- present in amla are effective in inhibiting the prolifera- rial, antifungal, antiviral, antidiabetic, hypolipidemic, tion of neoplastic cells in vitro and also in tumor-bearing antiulcerogenic, free radical scavenging, antioxidant, anti- animals. The hydrolyzable tannins of amla are also re- mutagenic, anti-inflammatory and immunomodulatory, ported to possess selective cytotoxicity to the human oral antipyretic, analgesic, antitussive, antiatherogenic, adap- squamous cell carcinoma and salivary gland tumor cell togenic, snake venom neutralizing, gastroprotective, lines, while they were nontoxic to the normal human antianemia, antihypercholesterolemia, wound healing, gingival fibroblasts. The dimeric compounds, oenothein antidiarrheal, antiatherosclerotic, hepatoprotective, ne- B, woodfordin C, and woodfordin D, were more effective phroprotective, and neuroprotective properties (Khan, than the monomeric compounds, while the macrocyclic 2009; Krishnaveni and Mirunalini, 2010). Compelling ellagitannin oligomers were more effective than gallic preclinical studies with both in-vitro and in-vivo systems acid and epigallocatechin gallate. These compounds also have shown that amla possesses anticancer, chemopreven- induced apoptosis in the neoplastic cells and mechanistic tive, cytoprotective, and radioprotective effects. Here, an studies showed that the effect was mediated by the attempt is made to analyze the role of amla in the prooxidant actions, but not through the generation of treatment and prevention of cancer. hydrogen peroxide (Sakagami et al., 2000). Amla as an antineoplastic agent Zhang et al. (2004) evaluated the antiproliferative effects Preclinical studies have shown that the aqueous extract of of 18 phytochemicals of amla (norsesquiterpenoids, amla causes a concentration-dependent cytotoxic effect on phenolic compounds, and proanthocyanidin polymers) L 929 cells in vitro and that the IC was observed to be 50 in B16F10, HeLa, and MK-1 cells in vitro. Among the 16.5 mg/ml (Jose et al.,2001).Theextractalsocaused norsesquiterpenoids, it was observed that the glycoside apoptosis in Dalton’s lymphoma ascites and CeHa cell lines phyllaemblicins B and C were highly potent in all the (Rajeshkumar et al., 2003). Khan et al. (2002) studied the three cells [B16F10 (GI50 at 2.0, 3.5 mg/ml, respectively), antiproliferative activity of the extract in the human tumor HeLa (GI50 at 3.0, 12.0 mg/ml, respectively), and MK-1 cell lines of different histological orgins (human erythro- (GI50 at 7.0 mg/ml for both compounds)]. However, with myeloid K562, B-lymphoid Raji, T-lymphoid Jurkat, respect to the phenolic compounds, all showed inhibi- erythroleukemic HEL) and observed it to be effective. tory activity against the three tumor cell lines (at a Recently, Ngamkitidechakul et al. (2010) have observed concentration of < 68 mg/ml), and were more effective that the aqueous extract of amla, which contains tannins against B16F10 than against HeLa and MK-1 cells. The (43%), uronic acid (11%), and gallic acid (21%), inhibited highes