.png){kind=icon}
Papaya leaves can cure cancer cognitive function many benifits uses. Pls read
papaya leaves contain a significant amount of nutrients to improve the immunity. Beside vitamins E, A, and C, they have vitamin B-17 whose concentrated form is used to cure cancer patients in conventional chemotherapy treatmen
Skip to main content
Log in
Access keysNCBI HomepageMyNCBI HomepageMain ContentMain Navigation
As a library, NLM provides access to scientific literature. Inclusion in an NLM database does not imply endorsement of, or agreement with, the contents by NLM or the National Institutes of Health.
Learn more: PMC Disclaimer | PMC Copyright Notice
PMID: 35720184
Carica papaya L. Leaves: Deciphering Its Antioxidant Bioactives, Biological Activities, Innovative Products, and Safety Aspects
Abstract
The prevalence of viral infections, cancer, and diabetes is increasing at an alarming rate around the world, and these diseases are now considered to be the most serious risks to human well-being in the modern period. There is a widespread practice in Asian countries of using papaya leaves (C. papaya L.) as herbal medicine, either alone or in combination with prescribed medications, to treat a variety of ailments. The importance of conducting the necessary descriptive studies in order to determine the safety of papaya leaf consumption is also emphasized in the context of their application in the healthcare sector. Electronic databases such as Google Scholar, Scopus, and PubMed were used to gather information on papaya leaves, their therapeutic potential, and clinical evidence-based studies. The literature was gathered from publications on papaya leaves, their therapeutic potential, and clinical evidence-based studies. The antidengue, anticancer, antidiabetic, neuroprotective, and anti-inflammatory effects of papaya leaves discussed in this article are supported by evidence from preclinical, in vivo, in vitro, and clinical trial studies, as well as from other sources. Leaves have been investigated for their mechanism of action as well as their potential to be used in the development of novel herbal products for the health business. According to the reports gathered, only a small number of research demonstrated that leaf extract at high concentrations was hazardous to certain organs. The collective literature reviewed in this review provides insights into the use of papaya leaves as a cure for epidemic diseases, highlighting the phytochemical composition and pharmacological attributes of papaya leaves, as well as the results of various preclinical and clinical studies that have been conducted so far on the subject. The review clearly demonstrates the successful medical evidence for the use of papaya leaf extracts in the healthcare system as a supplemental herbal medication in a variety of clinical settings.
Go to:
1. Introduction
Chronic diseases are becoming an increasingly serious hazard to public health, necessitating the implementation of nutrition-based strategies to combat them. It can be difficult to obtain medical care for certain disorders, and the consumption of staple functional foods is vital in terms of preventing such ailments. Medical care accounts for 10 to 20% of the changeable contributors to human health, whereas social determinants, specifically healthy eating habits, account for 80 to 90% of the adjustable contributors. Healthy plant-based diets are more environmentally friendly and are connected with a lower risk of obesity, type 2 diabetes mellitus, viral infections, and some malignancies, among other health benefits. When it comes to addressing chronic human diseases, functional agriculture, specifically the cultivation of functional food crops like papaya leaves (Carica papaya L.), has emerged as a new frontier in nutritional research. The creation of functional food crops employing cutting-edge technology in combination with approaches from crop science, food science, and preventive medicine is therefore a significant topic of research [1].
C. papaya L. belongs to the family Caricaceae and is commonly known as papaya, pawpaw, and kates. It is a perennial horticultural shrub originated from Mesoamerican Centre, Central America, and southern Mexico [2–4] and is mainly cultivated in the tropical and subtropical regions of Brazil, Australia, Malaysia, China, India, Thailand, Myanmar, Philippines, and other adjoining [5]. Papaya is not only cultivated for the ripe sweet fruit, even other parts of the plant such as seeds, leaves, roots, flowers, barks, and latex have been traditionally used worldwide for the preparation of various medicinal formulations [6, 7]. However, leaves have been emerged as one of the most useful parts with plethora of health-promoting compounds and activities. In traditional medicines, the decoction of papaya fresh leaves is added into a tea to cure malaria, whereas dry and cured leaves are used as cigar for smoking by persons suffering from respiratory disorders such as asthma. Fresh young leaves of papaya are consumed as a leafy vegetable after steaming in some countries. In India, boiled leaves of papaya are recommended by Ayurveda practitioners as relief from malarial and dengue fevers as papaya leaf extract is considered effective to elevate platelet count and red and white blood cells in patients after suffering from viral fever [8]. The extract has also been known to protect the patients against the sickling of red blood cells [9]. In many parts of Asia, papaya leaves are used for the treatment of beriberi [10]. Papaya leaves have been identified to have more than fifty bioactive components and therefore useful in the treatment of different human diseases [11, 12]. Scientific studies revealed the existence of considerable levels of glycosides, flavonoids, alkaloids, saponins, phenolic compounds, amino acids, lipids, carbohydrates, enzymes, vitamins, and minerals in papaya leaves [13, 14]. The crude form of ethyl acetate isolates of papaya leaves has very good antiplasmodial effect against Plasmodium falciparum and P. falciparum-resistant strains [15, 16]. Although the leaves of papaya are used in Ayurvedic medicines, the juice from green leaves has been gaining the attention of today's consumers as a functional food due to its potent antiviral and immunity-enhancing properties [17]. Tea prepared from the juice extracted from papaya leaves is also used as a synergistic therapeutic dietary supplement for patients suffering from the oxidative stress-related diseases because of its strong antioxidant potential [18]. Few of the studies reported that fresh papaya leaves possess antiseptic properties, while the dried leaves can be used as a tonic to purify the blood and to improve digestion. Leaf juice of papaya is now being known for its potent anticancer [19], antioxidative [4, 5], anti-inflammatory [7], antimicrobial [20], and antisickling properties [21] along with nephron protective [22], hepatoprotective [23], hypoglycaemic, and hypolipidemic effects [24] against toxins in the human system. In fact, polar isolates of papaya have exhibited antihuman immunodeficiency virus (HIV), analgesic, and wound healing properties [25]. The imbalance in the activity of free radicals and the cellular antioxidant system is implicated to various lethal conditions such as cancer and cardiovascular diseases [26]. Recent research studies have been focusing on all-natural antioxidant-enriched plant parts, and in particular, papaya leaves are currently being consumed because a medical assessment of the leaf extract exhibited antiproliferative activity on cancerous cells along with its immune modulatory effects. There is as significant number of reviews regarding the functional properties of papaya fruits, but limited reviewing available relevant to the phytochemicals, biological activity, medical studies, and scope of using papaya's leaves in health industry. Therefore, this review is aimed at bridging this gap for better utilization of papaya leaves in the future due to their great medicinal potential. Electronic databases such as Google Scholar, Scopus, and PubMed were used to gather information on papaya leaves, their therapeutic potential, and clinical evidence-based studies. The literature was gathered from publications on papaya leaves, their therapeutic potential, and clinical evidence-based studies. The antidengue, anticancer, antidiabetic, neuroprotective, and anti-inflammatory effects of papaya leaves discussed in this article are supported by evidence from preclinical, in vivo, in vitro, and clinical trial studies, as well as from other sources. Leaves have been investigated for their mechanism of action as well as their potential to be used in the development of novel herbal products for the health business. The collective literature reviewed in this review provides insights into the use of papaya leaves as a cure for epidemic diseases, highlighting the phytochemical composition and pharmacological attributes of papaya leaves, as well as the results of various preclinical and clinical studies that have been conducted so far on the subject. The review clearly demonstrates the successful medical evidence for the use of papaya leaf extracts in the healthcare system as a supplemental herbal medication in a variety of clinical settings.
Go to:
2. Phytochemical Composition of Papaya Leaves
Phytochemicals are chemical components, naturally found in different parts of plants, which make many species beneficial for therapeutic uses. Indeed, leaves of papaya are known to have various health-promoting phytochemicals, as it arose from chemical analysis performed in various studies which clearly illustrated the presence of significant amounts of alkaloids, saponins, glycosides, flavonoids, phenolic compounds, enzymes, amino acids, lipids, carbohydrates, vitamins, and minerals [13]. There were seven flavonoids found in papaya leaves, which were named as quercetin, kaempferol 3-rutinoside, quercetin3-(2G-rhamnosylrutinoside), quercetin 3-rutinoside, kaempferol 3-(2G-rhamnosylrutinoside), myricetin 3-rhamnoside. Caffeic acid, protocatechuic acid, quercetin, 5,7-dimethy coumarin, p-coumaric acid, and chlorogenic acid are among the phenolic substances found in the leaves [19]. There is evidence to suggest that leaves contain a wide range of phytochemicals, including carpaine, kaempferol 3-(2G-glucosylrutinoside), kaempferol 3-(2″-rhamnosylgalactoside), 7-rhamnoside, kaempferol 3-rhamnosyl-(1->2)-galactoside-7-rhamnoside, luteolin 7-galactosyl-(1->6)-galactoside, orientin 7-O-rhamnoside, 11-hydroperoxy-12,13-epoxy-9-octadecenoic acid, palmiticamide, and 2-hexaprenyl-6-methoxyphenol [25]. Due to these potent bioactive components, extracts of the aforementioned leaves can be used to prepare nutraceuticals and herbal medicinal formulations. Chemical constituent and structure of some important compounds of C. papaya leaves are illustrated in Figure 1. There were reports that C. papaya leaves were used with other herbs to heal ailments. Traditional doctors in Nigeria use it to treat diabetes, while in Cameroon, they combine it with other herbs to treat malaria and other fungal infections and aboriginal Australians' record using decoctions of the leaf as an anticancer remedy [16, 19]. The functional bioactive components of leaves of papaya can elevate the overall antioxidant potential of blood. The leaves of papaya plant are well known to have papain, cystatin, chymopapain, tocopherol, phenolic acids, cyanogenic glucosides, glucosinolates, and vitamin C as main phytochemicals [27]. Mainly alkaloids, saponins, glycosides, phenolic compounds, and flavonoids are responsible for the anti-inflammatory and anticancerous properties of papaya leaves [28]. Vitamins, minerals, and amino acids of papaya leaves are quite helpful to improve the total haemoglobin, proteins, and immunity of human system [29]. Carpaine along with dehydrocarpaine I and dehydrocarpaine II are most important health-promoting and major bioactive components found in the leaves of papaya. Due to the presence of carpaine, these herbal leaves are utilized in Ayurveda formulations for treating various physical disorders and viral fevers such as dengue and chikungunya. The aforementioned alkaloid has the ability to calm high blood pressure and fast heart rate and is effective for the uterus marked relaxation, the bronchioles dilatation, and movement of the intestinal strips along with antiplasmodial properties [30]. Carpaine has also been reported to have potent anticancerous and antihelminthic properties [31]. Its concentration has been reported the highest in mature leaves of papaya, i.e., 9.30 mg/g, followed by fruit pulp, i.e., 4.90 mg/100 g, fruit peel, i.e., 1.99 mg/100 g, and seeds, i.e., 0.65 g/g [32]. Leaves constitute different components in varying proportions such as 8.3% of carbohydrates, 38.6% of vitamin C, 5.6% of pro- and 0.23% of phosphoric acid. A good amount of tannin (0.85 ± 10−3 ± 1.76 ± 10−4 M, 0.824%) in papaya leaf extract has been reported by a few researchers [33]. Papaya leaves has been found to have highest total phenolic compounds as 424.89 ± 0.22 mg GAE/100 g of the dry sample followed by the 339.91 ± 9.40 in unripe papaya, 272.66 ± 1.53 in ripe papaya, and 30.32 ± 6.90 mg GAE/100 g in seeds [34]. Due to the aforementioned bioactive compounds, a very good antioxidant potential of 90% has been recorded in its leaves already. Researchers also reported a good concentration of calcium and magnesium, i.e., 3480 mg/kg and 5928 mg/kg, respectively; other minerals like iron (558 mg/kg), zinc (33.4 mg/kg), manganese (22.88 mg/kg), chromium (7.50 mg/hg), and
Figure 1
Chemical constituents and structure of some important compounds of C. papaya leaves. (a) Constituents of C. papaya leaves along with functional uses; (b) chemical structures of important bioactive compounds present in C. papaya leaves.
Go to:
3. Bioactivities of Papaya Leaf Extract
Papaya leaves have a very long history in terms of its medicinal uses and have been utilized in many Asian countries for treating various ailments. Because of the presence of the aforementioned important functional constituents, they are used to cure corns, warts, constipation, weakness, amenorrhea, menstruation problems, eczema, sinuses, cutaneous tubercle, glandular tumour, diabetes, ulcers, hypertension, dengue, etc. [8]. Traditionally, Australian aboriginal people consume papaya leaf extract for its anticancerous activity [36, 37]. In addition to their various cancer-fighting components, C. papaya leaves contain a significant amount of nutrients to improve the immunity. Beside vitamins E, A, and C, they have vitamin B-17 whose concentrated form is used to cure cancer patients in conventional chemotherapy treatment. Phytochemicals of papaya leaves have been reported to prevent bone marrow depletion and platelet destruction [2]. Juice of papaya leaf is quite helpful to elevate platelet count and red blood and white blood cells to normalize blood clotting and to repair the liver [18].
3.1. Antioxidant Effect
Many phytonutrients found in plants, such as fruits and vegetables, have come to the attention of food experts and the general public in recent years for their potential health benefits. Due to concerns about synthetic antioxidants' toxicity, these phytochemicals are commonly marketed as natural antioxidants as an alternative. Oxidative compounds present in many plants have antibacterial, antiviral, and cancer-fighting properties. They also have an array of other health benefits [19, 38]. Papaya peels are discarded after consuming the fruit. However, they contain antioxidants. Oxidative damage caused by free radicals has major implications in many chronic diseases [25]. By inhibiting the creation of free radicals, antioxidants can aid our health. New sources of natural antioxidants that are both safe and economically viable are now being investigated. Researchers made silver nanoparticles from C. papaya peel extract (CPPE) and examined their antioxidative properties to see if they worked. We found that the concentration-dependent activity of AgNPs was 56% for synthesised AgNPs and 38% for commercially available CPPE [39]. According to a recent study, the antioxidant activity of methanolic extract of papaya leaf was assessed by measuring its ability to neutralise free radicals (DPPH) [40]. DPPH free radical scavenging capacity was found to be best in hexane extract and lowest in aqueous extract in another investigation using papaya seed extracts and the results showed [41]. Papaya leaf antioxidant activity has been studied by Nisa et al. using various cultivars, maturities, and solvents. During extraction, the solvents were water, methanol, and 70% ethanol. Results showed that water-extracted mature leaves had the highest antioxidant activity of any of the other types of leaves tested. PaMsrB1 (plant methionine sulfoxide reductase B1) from papaya leaf was studied with Escherichia coli, which has MBP (maltose-binding protein) at its N terminal protease activity, which assists in the digestion of MBP-tag and leads to the separation of the recombinant PaMsrB1. In the presence of dithiothreitol, the purified recombinant protein PaMsrB1 demonstrated reductase activity against methionine sulfoxide (MetSO). An affinity chromatography and LC/MS/MS study discovered several proteins that interact with PaMsrB1. Understanding the defensive mechanisms of PaMsrB1 against antioxidative stress is facilitated by these findings [41]. Antioxidant activity and total phenolic content (TPC) were measured by Ang et al. to determine the antioxidative capability of C. papaya peels. Ferric reducing/antioxidant power (FRAP) and the ABTS radical cation inhibition activity (ABTS-RCI) were used to evaluate antioxidant activities, and the Folin-Ciocalteu method was used to measure TPC. The TPC of the papaya peel was 15.18 g GAE/mL when extracted with 90% acetone (v/v) for 60 minutes. DPPH, FRAP, and ABTS assays found antioxidant activity of 37.34%, 19.70 μg TE/mL extract, and 28.30%, respectively. The antioxidant potential of papaya peel may contribute to production of functional foods and nutraceutical in the near future utilising these papaya wastes [38]. Calvache et al. treated papaya peel residues with ethanol and drying them in a microwave oven to generate dietary fibre concentrates (DFCs), in order to demonstrate its antioxidant activity. Carotenoids, phenolics, ascorbic acid, proteocatechuic acid, manghaslin, quercetin 3-O-rutinoside, caffeoyl hexoside, ferulic acid, lutein, zeaxanthin, and beta-carotene were detected in the chromatographic analysis of the samples. Upon analysis of digestibility, it was found that about 65% of the polyphenols associated to peel DFCs were potentially bioaccessible in the small intestine and that the portion of indigestible fiber had antioxidant capacity [42]. In vitro antioxidant activity of papaya peel extracts, and their effects on endogenous glutathione, superoxide dismutase, catalase, cyclo-oxygenase-2 (COX-2), cyclo-oxygenase-3, and DNA fragmentation in HepG2 cells were investigated by Salla et al. Papaya peel extracts contained significant amounts of gallic acid (18.06 μg/g), caffeic acid (29.28 μg/g), p-coumaric acid (38.16 μg/g), ferulic acid (95.46 μg/g), and quercetin (3.17 μg/g). In vitro antioxidant capacity of papaya peels was determined by FRAP (31.86 μM Fe+2/g), trolox equivalent antioxidant capacity (14.56 mM trolox equivalents/g), oxygen radical scavenging activity (30.88 mM TE/g), and 2,2-diphenyl-1-picrylhydrazyl radical scavenging ability (IC50 = 8.33 mg/mL). SOD, CAT, GPx, GR activity, and GSH levels were decreased by 3.1, 1.46, 2.87, 1.34, and 1.32 times, respectively, when oxidative stress was induced. Papaya peel extracts, on the other hand, significantly increased SOD, CAT, GPx, GR, and GSH activities in cells compared to cells exposed to oxidative stress. It was found that papaya peel extracts caused cell death by apoptosis cells by significantly reducing COX-2 activity, increasing caspase-3 activity, and triggering DNA fragmentation. Anticancer activities of papaya peel extracts may be attributed to the synergistic action of free radical scavenging, stimulation of antioxidant enzymes, and triggering apoptosis [43]. Similarly, antioxidant properties are directly and indirectly contributing towards imparting other bioactivities such as immunomodulatory activities, antiviral, antidiabetic, and others discussed in following subsections. Table 1 provides an overview of C. papaya's antioxidant properties.
Table 1
Antioxidant activities of Carica papaya L. leaf extract.
Type of extractMethod usedResponsible phytochemicalsReferencesMethanolPeroxynitrite scavenging assayKaempferol 3-(2G-rhamnosylrutinoside)[41]Ethanol, methanol, and waterDPPH, FRAPFlavanoids[44]MethanolDPPHCarpaine, kaempferol 3-(2G-glucosylrutinoside), kaempferol 3-(2″-rhamnosylgalactoside), 7-rhamnoside, kaempferol 3-rhamnosyl-(1->2)-galactoside-7-rhamnoside, luteolin 7-galactosyl-(1->6)-galactoside, orientin 7-O-rhamnoside, 11-hydroperoxy-12,13-epoxy-9-octadecenoic acid, palmitic amide, and 2-hexaprenyl-6-methoxyphenol[25]MethanolDPPH—[45]n-Hexane, dichloromethane, ethyl acetate, ethanol, methanol, n-butanol, and waterDPPHPhenolics and flavonoids[46]AqueousDPPH, ABTSPolyphenols[5]MethanolPhosphomolybdenum methodFlavonoids[47]AqueousDPPH, ABTS+ assayProteins and phenolic groups[39]
Open in a separate window
3.2. Antiviral (Antidengue) and Antithrombocytopenic Effect
Dengue is an arboviral disease caused by dengue virus of the Flaviviridae family. Dengue fever occurs due to the infection transmitted by infected Aedes aegypti mosquito as a carrier of this virus [48]. The occurrence of this disease has increased by almost 30-fold in the previous three decades especially in developing countries. A number of infections caused by dengue virus ranges from 50 to 100 million per year [48], and every year, there is a new outbreak of dengue being reported. This viral infection leads to thrombocytopenia condition in infected patients [49]. The most common reason for thrombocytopenia is the poor production of platelets by the bone marrow, minimal survival of platelets, and sequestration of the platelets by the leptospirosis, malaria, dengue, and other viral infections. Major quantitative or qualitative dysfunction and reduction in the platelet count is the cause of mucocutaneous bleeding in the patients [50]. The platelet count drops below the normal level to an extent depending upon severity of viral infections. Moreover, viral fever is generally a self-limited illness which requires supportive care for complete recovery. Aspirin, antibiotics, nonsteroidal anti-inflammatory drugs, and corticosteroids must not be consumed by the patient as they are not so beneficial in viral infections. In fact, their consumption can cause gastritis or in severe cases internal bleeding too. One of the most disturbing aspects of the viral infections is that there are no effective antiviral agents available to treat their complications. In vivo studies have indicated quite beneficial effects of papaya leaf extract to improve immunity against infections and to increase platelet counts in thrombocytopenic patients after suffering viral infections [51].
Various studies both with animal and human models have been conducted by researchers worldwide to confirm the anti-inflammatory effect [7] and platelet count improvement after administration of simple papaya leaf extract or ethanolic aqueous extract [8, 52–54]. The use of papaya extract is recommended to get early recovery in case of dengue with low platelet and red and white blood cell count [54]. As per few case studies conducted in recent years, its positive effect on total plate count is clearly demonstrated. Researchers orally administered a 25 mL papaya leaf extract to the dengue patients daily in the morning as well as evening times for five days continuously [17]. There was significant improvement in platelet count and white blood cells and neutrophils (NEUT) just after the second day of oral consumption, and the count reached their healthy normal level at the end of course. Research was conducted, which is the study of multiple platelet transfusions to a baby suffering from congenital thrombocytopenia. The patient did not respond well to phototherapy, intravenous immunoglobulin, and two exchange
Figure 2
Antiviral (antidengue) and antithrombocytopenic effect of papaya leaves.
Like these aforementioned studies, there are various preclinical and clinical studies confirming the therapeutic effect of papaya leaves on thrombocyte animal models and are summarized in Table 2 for further enlightenment on its therapeutic potential against thrombocytopenia in dengue infection. The action mechanism of papaya leaf extract shows very good stabilizing properties to prevent platelet lysis and inhibits heat-induced and hypotonicity-induced haemolysis of erythrocytes even at the lower extract concentration. In the latter respect, the extracts are likely to possess membrane-stabilizing attributes and protect blood cells against stress-induced destruction. This property might be useful in patients with dengue where papaya leaf extracts could prevent platelet lysis, due to the presence of functional phytochemicals [56]. Some studies reported that papaya leaf extracts increase the arachidonate 12-lipoxygenase, 12S type activity, and platelet-activating factor receptor significantly in the body which consequently increases the platelet production in the patients administered with papaya leaf extract. The flavonoids present in this extract have also been found efficient in suppressing a protease found in viral assembly [57]. Further, Sharma et al. reported that papaya leaf extract was able to significantly increase the platelet count in thrombocytopenic rats. The authors also confirmed in vitro antiviral activity of papaya leaf extract using dengue-infected THP-1 cells (human leukemia monocytic cell line), and the possible mechanism noted was reduction in both envelop protein and NS1 protein expression. Further in thrombocytopenic rats treated with papaya leaf extract, decreased erythrocyte damage was observed along with increase in IFN-α expression and thrombopoietin levels indicating its potential to be used as therapeutic that can help in improving the platelet count and exhibit antiviral agent against dengue fever [58].
Table 2
Medicinal potential of Carica papaya L. leaf extract against virus-induced thrombocytopenia.
TreatmentResultsReferencesMature C. papaya leaf concentrate (0.72 mL/100 g bw of adult Wistar rats) administered for 3 days(i) Increase in platelet count without toxicity in rats
(ii) Increase in platelets by 76.50%, WBC by 30.51%, and RBCs by 9.08%[57]Fresh C. papaya leaf extract (0.2 mL (2 g)/mouse) for twenty-one days(i) Increment in the platelet and the RBC count.
(ii) The platelet count reached almost a fourfold higher at day 21 (11.3 × 105/μL) and RBC count in the test group increased from 6 × 106/μL to 9 × 106/μL at the end of treatment.[7]C. papaya extract (150 mL) daily to dengue patient for five days(i) Increase in no. of in thrombocytes (28 · 103/mL to 138 · 103/mL) and white blood cells BC (3000/mL · 7800/mL) in a dengue adult patient[52]Administration of 500 mg papaya leaf extract capsules on daily basis along with supportive medical treatment for five days to patients(i) Increment in platelet count
(ii) Third day onwards platelet count showed significantly positive results in the study group (82.96 ± 16.72) than control (66.45 ± 17.36). This trend of significant difference was the same on the fourth and fifth day of their studies.
(iii) Average platelet transfusion requirement in the study group was significantly less than the control group (0.685 units per patient vs. 1.19 units per patient)[59]Carpaine extracted from C. papaya leaf (2 mg/kg BW of thrombocytopenic Wistar rats) for twenty days(i) Isolated carpaine from C. papaya leaf extract exhibited potent activity in sustaining normal platelet counts without acute toxicity.[60]Aqueous extract of C. papaya leaves (one spoonful of leaf paste) extract on dengue-infected children for two days(i) Increase in number of a platelet count of dengue-infected children of age 10 and 14
(ii) After one-day administration, platelet count was 100,000 and within 2 days count reached up to 250,000[61]Aqueous extract of C. papaya leaves (25 mL) twice a day for two days(i) Significant increase in the platelet an white blood cell count after 2 days of treatment[62]Standardized C. papaya leaf aqueous extract (50 and 150 mg/kg BW of Wistar rats) for two weeks(ii) Oral administration showed a significant increase in thrombocytes (1014.83 cells/mm3), DTH response (0.16), and phagocytic index (63.15% increase)[63]C. papaya leaf extract capsules (290 mg) dose daily twice in thrombocytes postchemotherapy cancer patients for five days(i) After 5 days, the mean increase in platelet counts from 101.93 × 103/μL to 173.75 × 103/μL[64]Administration of papaya leaf extract (1.1 g) to total five hundred patients suffering from thrombocytopenia three times daily for five days(i) A significant increase in counts of platelets were noticed in the study group.[65]Treatment of infected mice with 1000 mg/kg bw of FCPLJ (freeze-dried C. papaya L. leaf juice content) for four daysIncrease in the number of total white blood cell and neutrophil counts by 1.44-fold.[66]
Open in a separate window
3.3. Anticancer Activity
Cancer is a huge group of diseases which can affect any organ of the human body with abnormal body cell growth. Cancer is also commonly known by the name of malignant tumour, and the cells affected by this disease have a tendency to spread from the originating organ to others very rapidly. Nowadays, cancer is one of the major causes of death worldwide, with 9.6 million estimated deaths due to this lethal disease in a year [67]. Prostate, lung, colorectal, liver, and stomach cancers are commonly found in males, while breast, colorectal, thyroid, lung, and cervical cancers are the most reported in females [68]. The burden of this disease is continuously growing in the world, exerting tremendous emotional and financial strain on patients, their families and health systems, especially in low- and middle-income countries. Alternative therapy includes different plant extracts and their bioactive ingredients responsible for tremendous health improvement, including the prevention and treatment of cancer in many countries [69].
In one of the patents filed, it was declared that proliferation of cancer cells reduced while health improvement was noted when people having cancer (lung, stomach, colon, pancreatic, liver, neuroblastoma, ovarian, breast, solid, and blood cancer) were treated with brewed extract of papaya leaf or fractioned components [70]. Researchers also found ethanolic papaya leaf extracts with high levels of saponins more beneficial in suppressing cancer cell lines than aqueous extracts [71]. However, although there are significant sources denoting the anticancerous effects of papaya leaves, only a few studies have identified their exact effect on cancerous cells and mechanism of action [72].
Medicinal value of herbs is dependent on the chemical constituents present in them which are known for their positive pharmacological and physiological activities inside human system. Research studies on papaya has clearly denoted that the whole plant has great number of secondary metabolites [73] and are directly linked with the potent anticancerous activities inside human body [74, 75]. Recent studies were conducted to evaluate the effect of capsules of papaya on cancer-affected patients split in different age groups (pediatric: 3-8 years and adult: 18-72), including males and females aged, with different body weights and ethnic backgrounds. They noticed a significant decrease in cancerous growth of the patients treated with papaya leaf extract of 0.16 g/kg body weight compared to control. Their findings suggested that papaya leaf extract has a great effect as anticancerous therapy for prevention and cure of prostate cancer due to presence of the phytochemicals (amino acids, flavonoids, alkaloids, and phenolics). However, the authors suggested that thorough research and understanding, the mechanism of action as anticancer agent is required before promoting use of papaya leaf extract as adjuvant treatment of cancer [37]. There are in vitro studies which clearly indicated a significant positive effect of this herbal extract on various tumour cell lines. However, still, further research needs to be conducted to provide concrete evidence and mechanism of action of papaya leaf extract as anticancer agent. Table 3 summarizes the results of studies conducted by various researchers to find out the medicinal potential of papaya against different kind of cancer cells.
Table 3
Medicinal potential of Carica papaya L. leaf extract against virus-induced thrombocytopenia.
TreatmentEffect on cancerous cellsReferencesAqueous isolate of C. papaya leaves (1.25–27 mg/mL)(i) Exhibited an effective anticancer property on cancer cell lines (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)
(ii) Suppressed DNA synthesis by inhibiting the incorporation of 3H-thymidine[70]Aqueous extract of C. papaya leaves (0.625–20 mg/mL)(i) Inhibition of proliferative responses of haematopoietic cell lines and solid tumour cell lines
(ii) Increase in the expression of immune modulatory genes[36]Brewed leaf juice (20 mg/mL)(i) Effective antiproliferative activity against cancerous cells of the prostate
(ii) Suppression of SCC25 cells growth in a dose-dependent manner
(iii) Survivability of 20% SCC25 cells, and 70% cancer-free human keratinocyte HaCaT cells remained viable with a dose of 20 mg/mL[37]Aqueous C. papaya leaf extract (659.63 μg/mL)(i) Antiproliferative and apoptotic induced effect of papaya leaf inhibits the proliferation of human breast cancer cell
(ii) Leaf extract exhibited apoptosis of MCF-7 cell line (22.54%)[76]Papaya leaf juice and its various extracts (0.25–0.1 mg/mL)(i) Effective antiproliferative activity against cancerous cells of the prostate
(ii) Potent growth inhibitory and cytotoxic activities on all prostate cells except the normal (RWPE-1 and WPMY-1) cells
(iii) Medium polar fraction inhibited migration and adhesion of metastatic PC-3 cells[77]C. papaya leaf juice (0.01-1 mg/mL) in prostate epithelial cancer cells, benign tumor, and human prostate cancer cells(i) Decrease the cancer cell proliferation
(ii) Arrest the S phase cell cycle
(iii) Induced apoptosis in prostate cancer cells[7]Silver nanoparticles (AgNPs) with papaya leaf extract (0.5, 1, 2.5, and 5 μg/mL) at 24 h and 48 h on human prostate carcinoma DU145 cells.Reduction in cell proliferation and subsequent apoptosis of human prostate carcinoma DU145 cells.[78]
Open in a separate window
Papaya leaf extract (PLE) has ability to interact with a huge range of molecular targets and exerts disease preventive activities. The major molecular targets included in the anticancer prevention are inhibition of the activity of DNA topoisomerase I/II and change of signaling pathways. Previous studies suggested that anticancerous properties of papaya leaves might be due to two reasons, i.e., caspase-3/7 process activation and activation of p53-dependent mitochondrial pathway [36]. However, some researchers also revealed that PLE seizes the PCa cell in S phase of cell division, which leads to the cell death, thus responsible for anticancerous activity [79]. Molecular signaling pathways and their cross-talk plays an important role in imparting the anticancerous activity such as repression of DNA topoisomerase I/II activities, lower gene expression of Bcl-2, CDK 4, cyclin D1, and B1, PCNA
Figure 3
Anticancer activities of papaya leaf extract.
Papaya leaf extract's immune modulatory potential is responsible for increasing the concentration of nitric oxide, CD80, TNF-alpha, and various other interleukins (IL-12p70, IL-12p40) and induction of apoptosis in cancer cells [37, 69]. However, papaya leaf extract at concentrations of 5 Ig/mL on the release of cytokines exhibited percent inhibition of TNF-α (10.8%), IL-1α (12.5%), IL-1β (27.4%), IL-6 (42.9%), and IL-8 (8.4%) reported in some studies [80]. Possible mechanism of papaya leaf extract to act as an anticancerous agent is to lower down metastatic cancer by decreasing the extracellular matrix concentration which further acts as a chemo-attractants of PC-3 cells for adhesion as well as migration [76]. Thus, the extract shows the potential to reduce the procreation of cancer cells and conquer the process of DNA synthesis [70]. It might be inferred a prominent correlation between secretion of Th1 type cytokines and increased cancer cell toxicity, which may result in the antitumour activity of papaya leaf extracts [36].
3.4. Immunomodulatory Effects
Other studies showed the immunomodulatory potential of papaya leaf extract and the cytokine ELISA profile of PBMC and revealed that papaya leaf extract downregulates IL-4 and IL-2 excretion in supernatants of cultures in a dose-reliant manner and presumed that leaf extract of papaya may bring apoptosis in PBMC, like similar effect on cancerous cells [36]. However, secretion of Th1 type cytokines like IL-12p70, IL-12p40, TNF-α, or IFN-γ applicable to anticancer immunity was interestingly upregulated even at low concentrations of leaf extract, with minor effect on IL-15, IL-6, IL-5, and IL-10 production 9 [37]. Th1 (IFN-γ+ CD4+) vs. Th2 (IL-4+ CD4+) T cells are important mediators of inflammatory reactions, and they may be influenced by regulatory T cells [81]. Flow cytometry was used by Abdullah et al. (2011) to investigate the effects of C. papaya on cells from healthy people. Significant downregulation of IFN-γ+ CD4+ T cells, upregulation of IL-4+ CD4+ T cells, and upregulation of CD3+ CD4+ CD25+ CD127- T cells were observed after papaya consumption. Regulatory T cells were upregulated in male participants' in vitro cultures, and this was significantly associated with levels of IL-1 in culture supernatants [82]. There is a possibility that leaf extract of papaya may promote the control of Th2-mediated allergic ailment, or as an adjuvant of various vaccines by promoting an alteration from Th2 to Th1 type immune response [6]. The methanol (MeOH) extracts of C. papaya and on mice for 3 weeks were able to decrease the level of proinflammatory cytokine, and it was also found that use of standardized CPL aqueous extract (SCPLE) was significantly increasing the thrombocytes and phagocytic index in thrombocytopenic rats [80]. These findings help the researchers to screen out the anticancerous effects of papaya leaves on cancer cells in vivo studies. Studies conducted by various researchers with regard to immunomodulatory potential of papaya leaf extracts are summarized in Table 4.
