Mol. Nutr. Food Res. 2013, 57, 153164 153DOI 10.1002/mnfr.201200388

REVIEW

Anticancer activity of Carica papaya: A reviewThao T. T. Nguyen, Paul N. Shaw, Marie-Odile Parat and Amitha K. Hewavitharana

School of Pharmacy, The University of Queensland, Brisbane, Australia

Carica papaya is widely cultivated in tropical and subtropical countries and is used as food aswellas traditional medicine to treat a range of diseases. Increasing anecdotal reports of its effectsin cancer treatment and prevention, with many successful cases, have warranted that thesepharmacological properties be scientifically validated. A bibliographic search was conductedusing the key words papaya, anticancer, and antitumor along with cross-referencing.No clinical or animal cancer studies were identified and only seven in vitro cell-culture-basedstudies were reported; these indicate that C. papaya extracts may alter the growth of severaltypes of cancer cell lines. However, many studies focused on specific compounds in papaya andreported bioactivity including anticancer effects. This review summarizes the results of extract-based or specific compound-based investigations and emphasizes the aspects that warrantfuture research to explore the bioactives in C. papaya for their anticancer activities.

Keywords:Anticancer / Antitumor / Bioactivity / Carica papaya / Nutraceuticals

Received: June 20, 2012Revised: September 16, 2012

Accepted: October 9, 2012

1 Introduction

Carica papaya belongs to the small family Caricaceae and isone of the major fruit crops cultivated in tropical and sub-tropical zones. Worldwide, the 2010 figures for papaya showthat over 11.2 million tons of fruits were produced in an areaof 438 588 Ha in 60 countries [1].

In traditional medicine, different parts of C. papaya in-cluding its leaves, barks, roots, latex, fruit, flowers, and seedshave a wide range of reputed medicinal application. In Ja-maica, the ripe fruit is used as topical ulcer dressings to pro-mote desloughing, granulation, healing, and reducing odorin chronic skin ulcers [2]. The green fruit is used for con-traceptive purposes by traditional healers in Pakistan, India,and Sri Lanka and for various human and veterinary diseasesin Nigeria such as malaria, hypertension, diabetes mellitus,jaundice, intestinal helminthiasis [3]. The leaves are used forcolic, fever, beriberi, abortion, asthma in India [4], and can-cer in Australia [5, 6]. The milky juice (latex) is employed asstyptic and as debridement when applied as external applica-tions to burns and scalds [3]. People in Lao, Cambodia, and

Correspondence: Dr. Amitha Kumudini Hewavitharana, School ofPharmacy, The University of Queensland, Brisbane, AustraliaE-mail: a.hewavitharana@pharmacy.uq.edu.auFax: +61-7-3346-1999

Abbreviations: BG, benzyl glucosinolates; BITC, benzyl iso-thiocyanate; IC50, the half maximal inhibitory concentration;MPLC, medium pressure liquid chromatography; MTT, (3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide

Vietnam use the latex to treat eczema and psoriasis [7]. Theseeds have been used as vermifuge, thirst quencher, or painalleviator [4]. The main traditional uses of different parts ofpapaya in various localities around the world are summarizedin Table 1.

Many of these traditional uses have been validated by sci-entific studies. Experiments have shown that C. papaya pos-sesses anthelmintic, antiprotozoan, antibacterial, antifungal,antiviral, antiinflammatory, antihypertensive, hypoglycemicand hypolipidemic, wound healing, antitumor, free-radicalscavenging, antisickling, neuroprotective, diuretic, abortifa-cient, and antifertility activities [3, 4, 810].

Among those conditions, it is interesting to note that therehave been anecdotal reports of patients with different types ofcancer achieving good results such as following consumptionof parts of papaya plant [5, 6]. The utility of herbal medicinesfor cancer treatment and prevention is receiving increasingattention due to the cost and side effects of current radiationor chemotherapeutic agents used for cancer patients, and thecontinuing increase in new cancer cases as well as cancerdeaths. Projections indicate that the deaths over the worldfrom cancer will rise to more than 13.1 million in 2030 [11].The purpose of this review is to conduct a literature search tounveil the scientific evidence that C. papaya may be of use inthe treatment and prevention of cancer.

2 Method

Different databases including PubMed, SciFinder, Web ofKnowledge, Scopus, and Embase were searched for studies

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154 T. T. T. Nguyen et al. Mol. Nutr. Food Res. 2013, 57, 153164

Table 1. Traditional uses of different parts of papaya in various localities [27]

Plant part Method of use Medicinal use and locality

Ripe fruit Fruit juice, topical ulcer dressings, cosmetic(ointment, soap)

Warts, corns, sinuses, and chronic forms of skin induration (scalyeczema, cutaneous tubercles) in Caribe, Philippines; chronic skinulcers in Jamaica

Stomachic, digestive, diuretic, expectorant, sedative and tonic,bleeding piles, and dyspepsia in India

Green fruit Juice Contraceptive and abortifacient in Pakistan, India, and Sri LankaMalaria, hypertension, diabetes mellitus, hypercholesterolemia,jaundice, intestinal helminthiasis in Nigeria

Latex Topical use Dermatitis and psoriasis in Africa, Asia, EuropeAbortion in India, Malaysia

Seeds Chewing, juice, powdered, paste, pessaries Abortifacient, anthelmintic, thirst quencher, pain alleviator,bleeding piles, and enlarged liver and spleen in West Indies andIndia

Leaves Fine paste, smoke, juice, infusion, decoction Heart tonic, febrifuge, vermifuge, colic, fever, beriberi, abortion,asthma in India

Rheumatic complaints in PhilippinesStomach troubles, cancer in Australia

Flowers Infusion, decoction Jaundice, cough, hoarseness, bronchitis, laryngitis, and tracheitisin Asia

Roots/barks Decoction, poultice, infusion Digestive, tonic, abortifacient in Australia, sore teeth in India,syphilis in Africa

investigating anticancer activities of C. papaya. The searchterms used were papaya and anticancer or antitumor.The reference lists of related articles were also reviewed foradditional relevant studies.

It is important to note that C. papaya is also known aspawpaw. Searching in some databases with the keywordpapaya also gave the results for pawpaw; however, thereare many reports of anticancer effect for a totally differentspeciespawpaw Asimina triloba in the family of Annonaceae.Therefore, the bioactive compounds and the anticancer prop-erties of C. papaya from the family Caricaceae (Fig. 1A) needto be well distinguished from that of pawpaw A. triloba (Fig.1B). Several articles have been found to include annonaceousacetogeninseffective chemotherapeutic agents in A. trilobaas bioactive compounds in C. papaya [1214].

3 Results and discussion

In our search, no human clinical trials were identified and noin vivo cancer studies have been conducted with extracts fromany part of C. papaya. Only several case studies have been re-ported in a patent as experimental examples with very limiteddata [15]. Case 1 was a 47-year old female with stomach can-cer that had metastasized to the pancreas. She drank about750 mL of papaya leaf extract everyday (one dried papaya leafwas boiled in a wooden vessel with 3000 mL of water untilconcentrated to 750 mL) for two 90-day periods with a 90-day break between two periods. The pancreatic metastasesdisappeared, the tumor marker, carcinoembryonic antigen,dropped from 49 to 2.3, and the alpha-fetoprotein droppedfrom 369 to 2.0, with no relapse found after. The other cases

were reported without any specific data, however, long-termsurvival was observed for five lung cancer patients, threestomach cancer patients, three breast cancer patients, onepancreatic cancer patient, one liver cancer patient, and oneblood cancer patient after drinking papaya leaf extract.

More surprisingly, the number of in vitro cancer studiesfor C. papaya was also limited to only seven cell culture-based studies. This review briefly details these studies andsummarizes the scientific evidence derived from them. Inaddition, some important phytochemicals found inC. papayawith previously reported cytotoxicity and anticancer activitiesare also included with their proposed mechanism of actions.

3.1 In vitro studies

The cytotoxic effect of C. papaya extract has been tested invarious cancer cell lines in in vitro studies summarized inTable 2 [5, 1520].

In 2002, Rahmat et al. [16] had screened the antipro-liferative activity on human breast and liver cancer celllines of pure lycopene and of both juice and extracted ly-copene from papaya and watermelon (two fruits with highlycopene contents). They reported that papaya juice and purelycopene caused cell death in the liver cancer cell line HepG2 with the half maximal inhibitory concentration (IC50) of20 mg/mL and 22.8 g/mL, respectively. However, neitherpapaya juice nor pure lycopene showed any effect on the cellviability of breast cancer cell MDA-MB-21. The extracted ly-copene from papaya juice did not display any effect on prolif-eration of either cell line. The lack of action of the extracted ly-copenewas explained bymultiple potential factors such as the

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Mol. Nutr. Food Res. 2013, 57, 153164 155

Figure 1. Papayapawpaw Carica papaya, Caricaceae (A) andPawpaw Asimina triloba, Annonaceae (B).

unsuccessful extraction process, the sensitivity of lycopeneto light and oxidation or microbial contamination duringtreatment.

Although papaya is a significant source of glucosinolatesandbenzyl isothiocyanate (BITC) [17,2125], whichhave beenextensively studied for their anticancer activities, there wasonly one in vitro study conducted by Nakamura et al. in2007 [17] for apoptosis induction and inhibition of super-oxide generation of n-hexane extract from papaya seed andpulp in comparison with authentic BITC. Biological effectssimilar to BITC, in inhibiting the superoxide generation andthe viability of acute promyelotic leukemia HL-60 cells, wereexhibited by the papaya seed extract (IC50 was 10 g/mL forgeneration of superoxide and 20 g/mL for viability) but notby papaya pulp extract even at a concentration of 100 g/mL.The experimental results suggested that these effects of pa-paya seed extractmay be due to electrophilic compounds suchas benzyl isothiocyanate.

The effects of papaya flesh extracts on the viability of breastcancer cell line MCF-7 were examined concurrently with ex-tracts fromother fruits in two studies byGarcia-Solis et al. [18]and Jayakumar et al. [19]. In these studies, the authors alsoevaluated antioxidants such as -carotene, polyphenols, andflavonoids in the fruits to focus on the contribution of theseantioxidants in the inhibition of proliferation. Among 14plant foods commonly consumed in Mexico (avocado, blacksapote, guava, mango, prickly pear cactus (nopal), pineap-ple, grapes, tomato, pear, grape, tomato, and papaya), Garcia-Solis found that only papaya had a significant inhibitory ef-fect on breast cancer cell growth. The extracts from papayaflesh at all five tested concentrations (0.01, 0.5, 1, 2, 4%) re-sulted in inhibition of proliferation of MCF-7 cells after a72-h treatment, in which the extract at concentration of 2and 4% caused 30 and 53% inhibition of cell proliferation,respectively. Interestingly, they found that the antiprolifera-tive effect in cancer cells did not correlate with total phenoliccontent or with antioxidant activity of the fruit extracts [18].In contrast, Jayakumar concluded that among 13 fruits ana-lyzed, chiku, pomegranate, dragon fruit, lichi, durian, grapeand apple, with higher sources of polyphenols and flavonoidsshowed more protective effects against nitric oxide-inducedproliferation ofMCF-7 cells. In this study, an ethanolic extractfrom papaya pericarp inhibited cancer cell growth and scav-enged nitric oxide (about 35% of nitric oxide was scavengedby the extract at concentration of 640 g/mL) [19].

In a study of Rumiyati et al., cytotoxicity was observedwhen another breast cancer cell line, T47D, was treated witha protein fraction containing ribosome-inactivating proteinsisolated from C. papaya leaves with an IC50 of 2.8 mg/mL[20]. The authors used immunocytochemistry to show theinduction of apoptosis via the mitochondrial pathway: inbreast cancer cells treated with the protein fraction, the tu-mor suppressor gene p53 expression was increased by about59.4% and antiapoptotic factor Bcl-2 protein expression wasdecreased by approximately 63% in comparison to controlcells.

In 2008, Morimoto et al. (15) patented the extremely higheffectiveness of a brew/extract of different parts of papaya inwater for the prevention, treatment, or improvement of manytypes of cancer: stomach, lung, pancreatic, colon, liver, ovar-ian, neuroblastoma, and other solid cancers or lymphoma,leukemia, and other blood cancers. Although only data thattested papaya leaf extract (1.2527 mg/mL) in an MTT assayand 3H-thymidine incorporation were shown, the anticancereffectswere concluded formany other parts (roots, stems, andfruit) of papaya plant. The authors carried out gel filtrationchromatography to fractionate papaya leaf extract accordingto molecular weight and measured the antitumor effect ofthe different fractions. They found two fractions that werecapable of suppressing the proliferation of the tested cancercell lines; one fraction containing components with molecu-lar weights of 1700, 1000, 700, and 300; and another fractioncontaining compounds with molecular weights of 1700, 100,600, 400, and 200. The compounds withmolecular weights of

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156 T. T. T. Nguyen et al. Mol. Nutr. Food Res. 2013, 57, 153164

Table 2. In vitro studies of extracts of different parts of Carica papaya

Cancer cell lines Treatment Results Reference

Breast cancer cell line (MDA-MB-231) Livercancer cell line (Hep G2) Chang liver cell line(normal cell)

Papaya fruit juice(0.2828 mg/mL), Lycopeneextracted from papayajuice,Pure lycopene (330 g/mL)

Pure lycopene and papaya juice inhibitedviability of liver cancer cell line Hep G2(IC50 = 22.8 g/mL and 20 mg/mL,respectively) but had no effect onbreast cancer cells or normal cells.Lycopene extracted from papaya juicedid not show any effect on either cellline.

[16]

Acute promyelotic leukemia HL-60 cells n-hexane extract of papayaseed or pulp (0.1100 g/mL),Pure benzylisothiocyanate (10 M)

Extract of seed: Dose dependentlyinhibited the superoxide generation(IC50 = 10 g/mL) and the viability ofcells (IC50 = 20 g/mL), comparable tothat of pure benzyl isothiocyanate.Extract of pulp had no effects at100 g/mL.

[17]

Breast cancer cell line (MCF-7) Aqueous extract of papayaflesh (0.014% v/v)

Significant inhibitory effect onproliferation of MCF-7 cells (p < 0.05)

[18]

Breast cancer cell line (MCF-7) treated withsodium nitroprusside, a nitric oxide donor

Ethanolic extract of papayapericarp (50640 g/mL)

Inhibited cell growth in MCF-7 cells(decrease in cell viability).Scavenged nitric oxide indose-dependent manner (about 35% ofnitric oxide was scavenged by extractat 640 g/mL)

[19]

Breast cancer cell line (T47D) Protein fraction containingRIPs isolated from leaves

The protein fraction possessedcytotoxicity: IC50 = 2.8 mg/mL).Induction of apoptosis by regulation ofp53 and BCl-2 protein expression((increased by 59.4% and decreased by63%, respectively).

[20]

Stomach cancer cell line (AGS)Pancreatic cancer cell line (Capan-1)Colon cancer cell line (DLD-1)Ovarian cancer cell line (Dov-13)Lymphoma cell line (Karpas)Breast cancer cell line (MCF-7)Neuroblastoma cell line (T98G)Uterine cancer cell line (Hela)T-cell leukemia cell line (CD26 negative ornegative Jurkat)

Aqueous extract of papayaleaves(1.2527 mg/mL)

Papaya leaf extract showed aconcentration-dependent anticancereffect on each of the cancer cell linesand suppressed DNA synthesis bysuppressing the incorporation of3H-thymidine.

[15]

T-cell lines (H9, Jurkat, Molt-4, CCRF-CEM,and HPB-ALL)Burkitts lymphoma cell lines (Ramos andRaji)Chronic myelogenous leukemia cell line(K562)Cervical carcinoma cell line (Hela)Hepatocellular carcinoma cell lines (HepG2and Huh-7)Lung adenocarcinoma cell line (PC14)Pancreatic epithelioid carcinoma cell line(Panc-1)Mesothelioma cell lines (H2452, H226, andMESO-4)Plasma cell leukemia cell line (ARH77)Anaplastic large cell lymphoma cell line(Karpas-299)Breast adenocarcinoma cell line (MCF-7)Mesothelioma cell line (JMN)Pancreatic adenocarcinoma cell line(Capan1)

Aqueous extract of papayaleaves (0.62520 mg/mL)

Inhibited the proliferative responses ofboth haematopoietic cell lines andsolid tumor cell lines.In peripheralblood mononuclear cells, papayaextract reduced the production of IL-2and IL-4 whereas increased theproduction of Th1 types cytokines suchas IL-12p40, IL-12p70, INF-, andTNF-.The expression of 23immunomodulatory genes wasenhanced by the addition of papayaextract.

[5]

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Mol. Nutr. Food Res. 2013, 57, 153164 157

Figure 2. Important phytochemicals found in Carica papaya.

1700, 1000, and 700 to 300 absorb UV with absorption peaksdetected at 260 nm.

Soon after, in 2010, Otsuki et al. [5] studied the effect ofsimilar aqueous papaya leaf extract (0.62520 mg/mL) on thegrowth of various tumor cell lines, including solid tumor celllines and haematopoietic cell lines. They found the prolif-eration of those cell lines was inhibited with no statisticaldifference between solid and haematopoietic tumor cell linesand proposed the induction of apoptosis as one of the mech-anisms involved in the growth inhibitory activity. In additionto this antitumor effect, the authors also reported the abil-ity of papaya extract to increase the production of Th1-typecytokines, such as IL-12p40, IL-12p70, INF-, and TNF- aswell as the expression of 23 immunomodulatory genes in pe-ripheral blood mononuclear cells. This study also attemptedto identify the functional fraction in the papaya leaf extract byperforming molecular weight cut off selection with a cellu-lose membrane tube. The active components with growth in-hibitory effect on tumor cells and immunomodulatory effectswere identified to be located in the fraction with molecularweight lower than 1000 [5].

3.2 Phytochemicals in C. papaya with reportedanticancer activities

In a review about major Australian tropical fruit biodiver-sity, Pierson et al. [26] noted that although papaya is a majortropical fruit, only a few pharmacological studies have beenconducted for C. papaya in comparison to other fruits. As

mentioned above, no in vivo and limited in vitro studies havebeen done to evaluate the effects of papaya extracts on cancer.In addition to these limited data, by indirect means, severalstudies claimed health benefits including protection againstcancer of C. papaya due to the antioxidant properties of pa-paya extract [2731]. However, there is continuous debateabout whether a high antioxidant activity is a good indicatorof high anticancer activity, and no conclusive proof has beendrawn thus far [32,33]. Therefore, further investigation is re-quired to assess the underlying mechanism of action ratherthan attributing the putative anticancer effects to antioxidantproperties of bioactive compounds in papaya.

Carica papaya contains a broad spectrum of phytochem-icals including enzymes (in the latex), carotenoids (in fruitsand seeds), alkaloids (in leaves), phenolics (in fruits, leaves,shoots), glucosinolates (in seeds and fruits) [4, 8]. Some im-portant phytochemicals found in C. papaya are presentedin Fig. 2. In the literature, among more than 5000 com-pounds from plants that have been identified to be associ-ated with anticancer properties [34], three groups of bioactivecompoundsphenolics, carotenoids, and glucosinolateshave attracted considerable interest in anticancer studies.Pure compounds of these three groups have been extensivelyresearched in in vivo and in vitro studies on many types ofcell lines for their potential effects in cancer treatment andprevention. These bioactives act via multiple mechanismssuch as cancer cell signaling, proliferation, apoptosis, migra-tion, invasion, as well as angiogenesis and carcinogen elim-ination [34, 5761, 78, 79, 108, 109] to exhibit in vitro and invivo anticancer activities. Their reported anticancer activities

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158 T. T. T. Nguyen et al. Mol. Nutr. Food Res. 2013, 57, 153164Table

3.Glucosinolates,phen

olicsan

dcarotenoidsin

Caricapap

ayaan

dtheirpotentialmechan

ismsforan

ticanceractivities

Compoundgroup

Methodofdetermination

Compoundsextracted

Rep

orted

anticanceractivities

andmechan

ism

ofactionofpure

compounds

Glucosinolates

HPLC

-UVat

230nm

forBG

and254nm

forBITC

Ben

zylg

lucosinolate

(BG):12.7

mol/g

seed

,