Sunday, April 22, 2018

Article Index

Custard Apple

Fruiticious Packaging

Dr A.P. George,
Agri-science Queensland,
Department of Employment, Economic Development and Innovation,
Maroochy Research Station, Nambour,
PO Box 5083, SCMC, Nambour, Australia 4560

Prepared February 2010

Technical Summary

  • The custard apple grown in Australia is a hybrid of the sugar apple (Annona squamosa) and the cherimoya (Annona cherimola).  More recently, hybrids have also been developed with Annona reticulata.  For centuries, Ayurvedic practitioners in India have extensively use various parts of the sugar apple (Annona squamosa) tree for the management of diabetes.  Similarly, Inca tribes in the Peruvian Andes have used cherimoya (Annona cherimola) as a medicinal plant.
  • The custard apple is a very sweet (up to 28% sugar) and aromatic fruit.  It contains significant quantities of vitamin C, thiamine, potassium, magnesium and dietary fibre.  Despite its high sugar content, the glycemic index of custard apple is low (54) and the glycemic load moderate (10.2).
  • Custard apple appears to possess potent bioactive principles in most of its plant parts (fruit, seed and leaves).  In this review, we present only the bio-activities of the fruit pulp.  Based on in vitro and in vivo testing, custard apple fruit exhibit potent anti-diabetic, anti-obese, anti-microbial and anti-cancer properties.
  • In Okinawan longevity studies, custard apple was identified as one of the few foods with anti-obese activity.  In animal studies, it reduced abdominal fat tissue by about 20%.
  • Aqueous extract of fruits of Annona reticulata were shown to be highly protective against chemical induced heart damage of rats.  In animal studies, custard apple fruit have been shown to reduce total cholesterol by 46%, triglycerides by up to 65% and the triglyceride/HDL ratio, a major predictor of heart disease in humans by half.
  • In anti-diabetic studies on animals, custard apple appears to mimic insulin stimulating its production and enhanced uptake of glucose by muscles leading to stabilisation of blood sugar concentrations.
  • Animal studies have shown that feeding sugar apple (Annona squamosa) pulp increased haemoglobin levels by up to 21%.  This response, if translated to humans, could provide a significant boost to athlete performance.
  • In vitro studies have shown that the fruit of Annona spp. have significant anti-microbial activities against a range of serious pathogens.
  • Currently the Annonaceae remain a "hot' family for the discovery of new anti-cancer drugs.  Custard apple contains a class of chemicals called acetogenins, which are very long chain fatty acids, and only found in Annonaceous species.  In vivo testing has shown that bullatacin, an acetogenin found in custard apple, to be 300 times more potent than Taxol (paclitaxel), a standard anti-cancer drug.
  • Limited human clinical testing trials are being conducted on the closely related Annonaceous species Asimina triloba (North American pawpaw) at the Nevada Cancer Clinic in the USA (visit www.pawpaw.research.com site for details).  Early findings appear promising.
  • Few fruits or foods possess the wide range of bioactivity exhibited by custard apple fruit and potentially it appears to be equal or even greater other superfruits such as blueberry.  Custard apple fruit can be processed into a range of health products from purees to cereal flakes to spray-dried powder.  Processed products may have a higher concentration of bioactive chemicals. 
  • Even though there have been limited animal and human studies, custard apple appear to be have excellent health and medicinal benefits which deserve to be further explored.

1.0 Health Trends

Cardio-vascular diseases (CVD) made up 16.7 million, or 29.2% of total global deaths according to World Health Report 2003 (WHO, 2003).  By 2010, CVD will be the leading cause of death in developing countries (WHO, 2007).  At least 20 million people survive heart attacks and strokes every year; many require continuing costly clinical care (WHO, 2007).  CVD is still Australia's greatest health problem. It kills more people than any other disease (accounting for 47 637 deaths in 2004) and affected 3.5 million Australians in 2004-05 (Australian Institute for Health and Welfare, 2006).  

Around 1 million Australian are estimated to have diabetes (Australian Government).  It is predicted that diabetes to soon to become the biggest global epidemic in history (Thompson, 2007).  Similar illness and disease patterns (obesity, type 2 diabetes, heart disease), currently experienced in developed countries, are now emerging in developing Asian countries (American Heart Association, 2007; Baylor College of medicine, www.lipidsonline.org; Medical News Today, 2006).  In 2002-03, Australian spent about $A10 billion on pharmaceuticals and $A70 billion on health (10% of GDP) (Australian Government).

In 2004, Australians spent $A1.8 billion on complementary medicines and therapies (Thompson, 2007). The global supplements and herbal medicine industry is growing at a rate of 10% per annum and is currently valued at $US 200 billion (Nutrition Business Journal, 2007).  It is expected to reach $US5 trillion by the year 2050 (Thompson, 2007).

Besides the benefits to human wellness and productivity, insufficient fruit and vegetable intake is estimated to cause some 2.7 million deaths each year and belongs to the top 10 risk factors contributing to mortality (Ezzati et al., 2002).  The World Cancer Research Fund has noted that consumption of at least five servings of fruit or vegetables a day was associated with about a 50% reduced risk of cancer; the cancer-preventative effects were dose dependent (www.wcrf).

2.0 Fruits And Health Benefits - Causality In Disease Prevention

The evidence on the health and medicinal benefits of custard apple presented in the following sections must be evaluated in terms of the strength of evidence or proof in prevention and intervention programs to show causal relationships.  This evidence is classified into four categories (WHO, 2003):

  • Insufficient evidence
  • Possible evidence
  • Probable evidence
  • Convincing evidence

There are various levels of testing to establish proof; these are outlined below in increasing order of sophistication and validity:

  • Observational studies (e.g. epidemiological, anecdotal, folk medicines etc.)
  • In vitro (test tube) testing using human cell lines
  • In vivo animal studies (tests on rats, rabbits etc.)
  • Human clinical trials (the best are randomised, double blind, placebo-controlled (RDBPC) experiments)

Human clinical trials are expensive and may cost several hundred thousand dollars to conduct.  Both in vitro (laboratory) and in vivo (live organism) testing has been conducted for custard apple, the latter on a limited scale.  There has been limited human clinical testing mainly on the anti-cancer properties of the closely related Annonaceous species Asimina triloba (www.pawpaw.research.com).


3.0 Research Into The Health Benefits Of Custard Apple

Compared with the major fruit and vegetables crops, the health and medicinal benefits of custard apple have been poorly researched presumably because they are less commonly known fruits.  With Annona spp., over 600 research papers have been published.  Most papers have been published in the last ten years.  Most of the medicinal research conducted on Annona spp. has concentrated on its anti-cancer properties due to a class of compounds called acetogenins which are specific to various plant organs of Annonaceae.

4.0 Scope Of The Review

The health and medicinal properties of Annona spp. hybrids has been previously reviewed by George et al. (2006).  A collection of over 600 references has been catalogued and held by Agri-research Queensland (George et al., 2006).  

This shorter review restricts itself to the health and medicinal benefits of the custard apple fruit and not to other plant organs of this species even though the leaves or seed have also been shown to possess significant bioactivity.  Because custard apple is a hybrid between several species viz. Annona squamosa, Annona cherimola and Annona reticulate, we have reviewed findings for each of these three species individually as well as for the hybrids.

5.0 Historical/Ethno-Botanical Perspective

Annona species have been widely grown throughout Central and South America.  The fruits of cherimoya are native to the subtropical regions of Peru and Ecuador and are grown at elevation of 800-1200 metres.  Images of the fruit are depicted on the pottery of the Inca tribes in the Andean mountains in these countries (Bonavia et al. 2004).  Various parts of the tree were used for health and medicinal purposes (Pinto et al., 2005).  In India, Ayurvedic practitioners have intensively used the young leaves of sugar apple (Annona squamosa) for the management of diabetes (Atique et al., 1985; Topno, 1997). 

6.0 Nutritional Composition

Custard apples are usually consumed as dessert fruit.  The fruit is rich in starch when firm but increases markedly in sugar as it softens.  The main sugars are glucose and fructose (80-90%).  Compared with other fruits, custard apple fruits contain significant quantities of vitamin C, thiamine, potassium, magnesium and dietary fibre (Table 1).  The calorific value is high (300-450 kJ per 100 g) and is almost double that of peach, orange and apple.

Nutrient composition of custard apple (Annona spp. hybrids) per 100g of ripe fruit. (Various sources: Leung and Flores, 1961; Wenkam, 1990; USDA, 2002; Janick and Paull, 2006).

Proximate   Minerals   Vitamins  
Water (%) 70-80 Calcium 10-25mg ascorbic acid 10-300mg
Energy Kcal 95-110 Iron 0.3-0.6mg thiamin 0.05-0.11mg
             KJ 300-450 Magnesium 21-32mg riboflavin 0.07-0.11mg
Protein (%) 1.0-2.0 Phosphorus 20-40mg niacin 0.8mg
Lipid (fat) (%) 0.3-0.6 Potassium 250mg vitamin A 0-6IU
Sugar (%) 18.0-24.0 Sodium 4.5-9mg vitamin B6 0-0.2mg
Fiber (%) 0.05-4.5     vitamin E 0.6mg
Ash (%) 0.4-0.8     panthothenic acid 0.2mg

However, despite its high sugar content the glycemic index of custard apple is low (54) and the glycemic load moderate (10.2) (Brand-Miller et al., 2003).


7.0 Bioactive Phytochemicals

7.1 Phytochemicals

The bioactive phytochemicals in custard apple are those that are related to its health and medicinal activity.  These phytochemicals are mainly phenolic and flavonoid compounds, which are largely responsible for antioxidant activity.  These bioactive chemicals can vary widely within Annona spp. hybrids (Noichinda et al., 2009).  

The bioactive chemicals in custard apple and closely related species have been evaluated in many studies (Bhakuni, et al. 1972; Idstein et al.1985; Bartley, 1987; Wylie et al. 1997; Rios et al. 2003, Yu, et al. 2005, Pino et al. 2006; Noichinda et al., 2009).  

To date, the main bioactive phytochemicals found in Annona spp. fruit include:

  • Acetogenins - polyketide fatty acids (>300)
  • Aliphatic ketones e.g. palmitone
  • Alkaloids (>32)
    • aporphine
    • benzylisoquinolines
    • protoberberine
    • tetrahydroisoquinolines
  • Benzenoids (>19)
  • Cyclic peptides
  • Essential oils (>60)
  • Lignans (>15)
  • Long chain fatty acids (oleic, linoleic, palmitic, stearic found in seed)
  • Organic acids (47) hexanoic, and octanoic
  • Terpenoids,
    • monoterpenoids (>60%)
    • diterpenoids
    • kauranes (72)
    • sesquiterpenoids
  • Purines
  • Steroids
  • Tryptamine-derived amides
  • Volatiles (>180)

7.2 Volatiles and flavour components

Several studies (Bartley, 1987; Wong and Khoo, 1993; Wylie et al. 1997; Andrade et al., 2001; Rios et al. 2003; Yu, et al. 2005; Pino et al. 2006; Shashirekha, et al. 2008) have reported on the major volatiles found in custard apple fruit and closely related species.  These are presented below.

  • α-pinene
  • β-pinene
  • limonene
  • bornyl acetate
  • germacrene D

The volatile compound found in greatest concentration in custard apple fruit is pinene, a bicyclic terpene known as a monoterpene.  There are two structural isomers found in nature: α-pinene and β-pinene.  As the name suggests, both forms are important constituents of pine resin; they are also found in the resins of many other conifers, and more widely in other plants. 

7.3 Acetogenins

One class of chemicals which sets custard apple apart from other fruit species is the presence of acetogenins (McLaughlin, 2008).  The acetogenins are unique to the Annonaceous family and in in vitro and in vivo studies appear to have considerable anti-cancer properties (see later sections).  Many of the compounds appear to have multiple physiological activity e.g. some acetogenins have both anti-cancer and anti-hypertensive activity. 


8.0 Antioxidant Activity

Studies report widely differing levels of anti-oxidants in Annona spp.  Studies conducted in India (Kaur and Kapoor, 2005), Taiwan (Chen, et al. 2006), and Costa Rica (Franco, 2006) show that Annona squamosa, Annona cherimola and Annona muricata have high anti-oxidant activity.  In contrast, a DPI&F study (Treloar, 2006; unpublished data) showed that Annona spp. hybrids have very low levels of antioxidants.  These discrepancies may be due to varietal differences, method of analyses or time of sampling.  

In the Taiwanese study (Chen, et al. 2006), the antioxidant activity in mature fruits of 36 species and varieties produced in Taiwan was analysed by the ferric reducing antioxidant power (FRAP) assay.  In this study, sugar apple was categorised as having very high antioxidant activity >70mmol/100g edible part.

9.0 Effects On Cardio-Vascular Disease

Hole et al. (2006) studied the effects of fruit pulp of Annona reticulata L. fruits (ARF) on heart disease in rats.  They selected the aqueous extract of dried fruits of Annona reticulata (ARF) because it was found to possess significant in vitro antioxidant potential in preliminary screening.  Hole et al. (2006) tested the protective effect of aqueous extract of the fruits on isoproterenol induced myocardial infarction (death of heart tissue) in rats.  ARF was administered orally in two different doses (100mg/kg, 200mg/kg) for 21 days.  Histopathological observations of the heart tissue of rats challenged with isoproterenol showed confluent necrosis (death), separation of muscle fibers and inflammatory infiltrations. ARF pre-treatment protected these morphological changes, thus supporting evidence for the cardioprotective activity of ARF (Figure 1).

Hole et al. (2006) concluded from their studies that  chronic oral administration of ARF 100 and 200 mg/kg prevented isproterenol-induced alterations in lipid profile, marker enzyme activity, endogenous antioxidant levels and cellular damage wherein the results are comparable with captopril (a drug used to treat heart failure), which was used as a positive control in the study.  

Assuming that bioavailability in rats is similar to humans, for an 80 kg human, this would be equivalent to eating 80 g (or about 16 g dried) of fresh pulp (about a quarter segment of normal size custard apple fruit) per day.

Figure 1.

 

plate1
Plate 1: Photomicrographs of heart section from rat from normal group.

plate2
Plate 2: negative control group treated with a chemical to induce death of heart tissue.
plate3
Plate 3: Annona reticulata pulp 100 mg/kg.
plate4
Plate 4: Annona reticulata pulp 200 mg/kg.
Plates 3 and 4 show the protective effect of Annona reticulata pulp as tissues more closely resemble the control group in Plate 1.

10.0 Effects On Lipid Profiles

The studies by Hole et al. (2006) showed that pulp of Annona reticulata could significantly reduce total cholesterol, decrease low density lipoprotein and triglycerides (both these latter cholesterol types are classified as bad cholesterol) and increase high density lipoproteins (HDL is classified as good cholesterol) of rats treated with a chemical to induce heart disease (Figure 2).

In another study, (Gupta et al., 2005a) showed that fruit pulp of sugar apple (2.5-5.0 g/kg body weight) reduced total cholesterol level by 46% in normal and 32.4% in diabetic rabbits with increased HDL-cholesterol (Figure 3).  

Assuming that bioavailability in rabbits is similar to humans, for an 80kg human; this would be equivalent to eating a 400g, or about 80g dried, of fresh pulp (about a normal size custard apple fruit) per day.

The triglyceride/HDL ratio in the rabbits, a major predictor of heart disease in humans (Gaziano et al., 1997), was halved (Figure 4).

figure2

figure2a
Figure 2. Effects of dried Annona reticulata fruit (ARF) on lipid profile of rats isoproterenol-induced to produce myocardial infarcts (Hole et al., 2006).  MI=Induced myocardial infarct (heart disease). CHOL=cholesterol, HDL=high density lipoprotein, LDL=low density lipoprotein, TRIGLY= triglyceride.

figure3

Figure 3.  Effect of feeding sugar apple (Annona squamosa) fruit pulp (5g/kg) for one month on lipid profile of normal and diabetic rabbits (Gupta et al., 2005a).  CHOL=cholesterol, HDL=high density lipoprotein, LDL=low density lipoprotein, TRIGLY= triglyceride.

figure4

Figure 4. Effects of feeding sugar apple (Annona squamosa ) fruit pulp (5g/kg) for one month on triglyceride/HDL ratio of rabbits, a major predictor of heart disease in humans (based on Gupta et al., 2005a).


11.0 Anti-Obese Activity

Several studies have examined why villagers on the island of Okinawa have extended longevity (Niwano et al., 2009).  These studies involved large scale screening of Okinawan plant foods to determine factors associated with the prevention of adipogenesis (development of fat cells) and promotion of adipolysis (digestion of fats) (Beppu et al., 2009; Niwano et al., 2009).  Custard apple was listed as one of the foods with strong anti-obese activity (Niwano et al., 2009).  Custard apple is regularly consumed by the Okinawan population.  Beppu et al. (2009) showed that oral administration of ethanol extracts of fresh custard apple fruit potently lowered plasma triglyceride concentrations by 65% of KKAy mice fed a moderately high fat diet for four weeks (Figure 5) and exhibited a potent inhibitory effect on adipogenesis reducing fat tissue by about 20% (Figure 6).  

Figure 5. Effects of ethanol extracts of mature fruit of custard apple on triglyceride concentrations of KKAy mice fed a moderately high fat diet (Beppu, et al., 2009).Figure 5. Effects of ethanol extracts of mature fruit of custard apple on triglyceride concentrations of KKAy mice fed a moderately high fat diet (Beppu, et al., 2009).


Figure 6.  Effects of ethanol extracts of mature fruit of custard apple on abdominal adipose tissue weight of KKAy mice fed a moderately high fat diet (Beppu et al., 2009).Figure 6.  Effects of ethanol extracts of mature fruit of custard apple on abdominal adipose tissue weight of KKAy mice fed a moderately high fat diet (Beppu et al., 2009).

Assuming that bioavailability in mice is similar to humans, for an 80 kg human, this would be equivalent to eating a 50 g (or about 10 g dried) of fresh pulp (about an eight of a normal size custard apple fruit) per day.


12.0 Anti-Diabetic Properties

Anti-diabetic properties of Annona spp. appear to be related to stimulation of insulin production and enhanced uptake of glucose by muscles leading to stabilisation of blood sugar concentrations (Gupta et al., 2005a).  Studies in rabbit showed that 5 g of semi-dried pulp of sugar apple per kg of body weight was effective as an anti-diabetic treatment (Figure 7).  

Assuming that bioavailability in rats is similar to humans, for an 80 kg human, this would be equivalent to eating a 40 g (or about 10 g dried) of fresh pulp (about an eight of a normal size custard apple fruit) per day.

Leaf extracts are also effective in lowering blood glucose levels and several reports indicates that Annona squamosa leaf extract can substitute effectively for externally administered insulin (Gupta et al., 2005b; Kaleem et al., 2006; Rabintossaporn et al., 2009).  

Figure 7. Effects of feeding sugar apple (Annona squamosa) pulp (2.5 to 10g/kg) for 1 month on urine sugar levels in diabetic rabbits (Gupta et al., 2005a). AS = Annona squamosa.

Figure 7. Effects of feeding sugar apple (Annona squamosa) pulp (2.5 to 10g/kg) for 1 month on urine sugar levels in diabetic rabbits (Gupta et al., 2005a). AS = Annona squamosa.


13.0 Effects On Blood Haemoglobin

Gupta et al. (2005a) also showed in their rabbit studies that feeding sugar apple (Annona squamosa) pulp increased haemoglobin levels by up to 21% (Figure 8).  This response, if translated to humans, could provide a significant boost to an athlete's performance.

Figure 8.  Effects of feeding sugar apple (Annona squamosa) fruit pulp for one month on total haemoglobin concentrations in normal and diabetic rabbits (Gupta et al., 2005a)

Figure 8.  Effects of feeding sugar apple (Annona squamosa) fruit pulp for one month on total haemoglobin concentrations in normal and diabetic rabbits (Gupta et al., 2005a)


14.0 Anti-Cancer Properties

Difficulties with most of the chemotherapeutic drugs emanate from their concurrent eradication of normal healthy cells, including those responsible for immunity (www.pawpaws.net, 2010).  Tumor cells grow and replicate more rapidly than normal cells.  This is because they are better equipped to receive glucose, a good source of energy for fast replication.  Also, cancer cells quickly develop a network of blood vessels (angiogenesis) to ensure an efficient supply of nutrients and oxygen.  This is partly why cancer patients lose weight; the cancer cells rapidly take up nutrients meant for normal cells.  Furthermore, with chemotherapy cancer cells develop resistance to the drugs, rendering chemotherapy useless and futile after a period of remission (www.pawpaws.net, 2010).  

Cancer cells smartly find a way of protecting themselves from the damaging effects of drugs. They generate what is called the ABC transporter superfamily, which transports a variety of substrates including amino acids, sugars, inorganic ions, polysaccharides, peptides, and proteins into the cells (Yong-Ju Liang et al., 2009).  In cancer cells, a member of this superfamily, called the multidrug resistant (MDR) protein, is overexpressed and helps to pump drugs out of the cancer cells, making the cancer cells simultaneously resistant to a variety of drugs.  Thus, the cancer cells are protected from the toxic effects of drug combinations (www.pawpaws.net, 2010).

14.1 Discovery of acetogenins

The anti-cancer properties of custard apple appear to be mainly due to a class of compounds called acetogenins which are specific to Annonaceaous species (Alai et al., 1999; McLaughlin, 2008).  Acetogenins are very long chain fatty acids (McLaughlin, 2008).  Throughout the 1990s, a team of researchers lead by Professor Jerry McLaughlin at Purdue University, in West Lafayette, Indiana, and another team at Kaohsiung Medical University, Kaoshiung Taiwan have evaluated the structure and anti-cancer properties of acetogenins.  

To date, over 400 acetogenins have been identified (McLaughlin, 2008; Li et al., 2008).  Currently the Annonaceae remain a "hot' family for the discovery of new anti-cancer drugs.  Chinese and Taiwanese universities have successfully synthesized a range of these acetogenins (Li et al., 2008).

14.2 In vitro testing

Acetogenins have been tested in vitro against 60 types of cancer cells, including breast, prostate and colon (Fang-Rong et al. 1999; Alai et al., 1999; Chih et al., 2001; McLaughlin et al., 2005; McLaughlin, 2008).  Leaf and seed extracts of acetoegnins exhibited powerful in vitro cytotoxic and anti-cancer properties, up to 200-300 times more powerful than some currently used drugs such as Taxol (McLaughlin, 2008).  

Thus far, specific acetogenins have been reported to be selectively toxic in vitro to the following types of tumour cells (Fang-Rong et al. 1999; Chih et al., 2001; McLaughlin et al., 2005; McLaughlin, 2008).

  • lung carcinoma cell lines
  • human breast solid tumour lines
  • prostate adenocarcinoma
  • pancreatic carcinoma cell lines
  • colon adenocarcinoma cell lines
  • liver cancer cell lines
  • human lymphoma cell lines
  • leukaemia
  • multi-drug resistant human breast adenocarcinoma

14.3 In vivo (living organism) testing

McLaughlin et al. (2006) showed that the acetogenin, bullatacin, was active in reducing the development of leukaemia in mice.  Compared with Taxol (paclitaxel) a standard anti-cancer drug, bullatacin was 300 times as potent as taxol in this in vivo test system.  Cuendet et al. (2008) showed that Asimina triloba extract containing acetogenins increased mammary tumour latency from 55 to 66 days in Sprague-dawley rats.

14.4 Human clinical trials

Limited human clinical testing trials are being conducted on the closely related Annonaceous species Asimina triloba (North American pawpaw) at the Cancer Screening and Treatment Centre in Nevada, USA with apparent promising results (visit www.pawpaw.research.com site for details).  A standardized pawpaw extract called Pawpaw Cell-Reg, containing mixtures of Annonaceous acetogenins and capsules of dried sugar apple pulp are being sold commercially. 

14.5 Mode of action

Annonaceous acetogenins may be good chemotherapeutic agents for cancer (Ahammadsahib et al., 1993; Oberlies et al., 1995, 1997; Chih et al., 2001).  These compounds inhibit mitochondrial and cytoplasmic production of adenosine triphosphate (ATP), which is the major source of energy for the cells and also a precursor of the nucleotides needed to produce DNA and RNA. Annonaceous acetogenins also inhibit the enzymes of complex I in the electron transport system in mitochondria (Oberlies et al., 1999, McLaughlin, 2008; McLaughlin et al., 2010).  They also inhibit the NADH oxidases found in the plasma membranes of tumor cells (McLaughlin, 2008).  Their net effect is depletion of ATP levels.

Tumor cells, being typically metabolically more active, are more susceptible than normal cells to the effects of the acetogenins (McLaughlin, 2008).  For example, breast cancer cells can take glucose seventeen times faster than normal cells.  Angiogenesis requires ATP and angiostatin blocks angiogenesis by inhibiting ATP synthase (McLaughlin, 2008).  Thus, ATP depletion helps to block the growth of new vessels to nourish tumors

Annonaceous acetogenins also thwart multi drug resistant (MDR) tumor cells (Oberlies et al. 1997).  The protein pumps (glycoproteins), which extrude the drugs from the tumor cells are energized by ATP.  Thus, by depleting ATP, the glycoproptein pumps become dysfunctional.  

Acetogenins can also induce apoptosis (programmed cell death) of certain cancer cell lines (Yong-Ju Liang et al., 2009) (Figure 9).  Apoptosis is an important mode of action for many antitumor agents.  It is a protective measure against malignant transformation; in fact effective tumor therapy may involve the induction of apoptosis.

Many acetogenins are more potent than some of the standard drugs currently used to treat cancer.  For example, the acetogenin bullatacin is 258 times more cytotoxic against breast cancer cell line MCF-7/Adr than adriamycin (Oberlies et al., 1997; McLaughlin, 2008).

Figure 9. Treatment with bullatacin resulted in significant apoptosis (programmed cell death) of KBv200 multidrug resistant human epidermoid carcinoma cell lines (Yong-Ju Liang et al., 2009).

Figure 9. Treatment with bullatacin resulted in significant apoptosis (programmed cell death) of KBv200 multidrug resistant human epidermoid carcinoma cell lines (Yong-Ju Liang et al., 2009).

14.6 Activity in custard apple fruit

There is limited information of the concentrations of acetogenins in custard apple fruit.  Bullatacin, isolated from the fruit of custard apple, is one of the most potentially effective antitumor Annonaceous acetogenins (Oberlies et al., 1997).  Bullatacin is 258 times more cytotoxic against MCF-7/Adr than adriamycin.  

Taiwanese studies (PhD thesis (ID: 082KMC03068005, unnamed author) showed that the methanolic extracts of the fresh fruits of Annona squamosa (Annonaecae), contained significant cytotoxicity against in vitro tissue culture cells in:

  • human A-549 lung carcinoma
  • murine P-388 lymphocytic
  • HIV replication in H9 lymphocyte cells

Champy et al. (2005) showed that soursop (Annona muricata) fruit appear to contain significant quantities of annonacin.  Fruit pulp and fruit nectar had concentrations of annonacin that were 100 times higher than in the aqueous leaf extracts.  

McLaughlin (2003) and Pomper et al. (2009) showed that fruit of Asimina triloba, a close relative of Annona spp., also had significant concentrations of active acetogenins.  In the USA, the fruit of Asimina triloba are called pawpaw.  This north American pawpaw should not to be confused with the pawpaw grown in Australia which belongs to the Carica spp.


15.0 Anti-Microbial/Viral/Fungal Activity

The fruit of Annona spp. have been shown to have anti-microbial activities (Wiart et al., 2005) due to several compounds including:

  • Ent-kauranes
  • Acetogenins
  • Essential oils
  • Benzylisoquinolines alkaloids

Wiart et al. (2005) showed good anti-bacterial activity of the crude methanol extract of sugar apple fruit, and an isolated diterpene, against Staphylococcus aureus (sometimes called golden staph) and Streptococcus pneumoniae.  They suggested that that the extract could be a good source as a food preservative and as an antibiotic.  

Rios et al. 2003 showed in vitro antimicrobial activity of three essential oils of cherimoya fruit against five Gram (±) bacteria (Table 2).  Wu et aI (1996) found that kaurane diterpenoids in the fruits of Annona squamosa showed significant activity against HIV replication in H9 lymphocyte cells with an EC50 value of 0.8 ?g/mL (therapeutic index >5).

TABLE 2.
Antimicrobial activity of the essential oils of leaves, flowers and fruits from cherimoya (Annona cherimola) (Rios et al., 2003). Note that the lower the concentration the more effective as a therapeutic agent.

  Minimum inhibitory concentration (mg/mL)
Sample Staphylococcus Enterococcus Escherichia Shigella Proteous Candida
  aureus faecalis coli sonei mirabilis albicans
Leaves 0.25 0.5 10 5 5 5
Flowers 0.125 0.5 2 2.5 2 0.5
Fruits 0.06 0.5 2 2.5 1 2
Caryophyllene 80 16 16 16 > 16 > 16
Terpinolene > 16 > 16 > 16 > 16 > 16 > 16
Linalool 2 4 2 2 2 4
?-Pinene > 16 > 16 > 16 > 16 > 16 > 16
?-Pinene 16 16 4 16 16 8
? -fenchyl alcohol 4 2 2 2 2 8
Gentamicin 0.004 0.004 0.008 0.008 0.008 -
Nystatin (antifungal drug) - - - - - 0.004

16.0 Health Products

Custard apple can be processed into a wide range of products from purees, cereal flakes to spray dried powder (Rajarathnam et al., 2003; Shashirekha, et al., 2008).  The Australian custard apple industry has developed two commercial processing factories to produce frozen puree (Figure 10).  We expect that processed products will have a higher concentration of bioactive chemicals than the fresh fruit.  We suggest that custard apple could be promoted as a health product either as the fresh fruit, puree or dried product.

Figure 10. Processed custard apple puree which could be developed into a health product.

Figure 10. Processed custard apple puree which could be developed into a health product.


17.0 Comparative Studies With Other Fruits

Few fruits have the wide range of bioactivity exhibited by custard apple fruit even those that are already considered superfruits such as blueberry and pomegranate.  Even though there have been limited animal and human studies, custard apple fruit appear to be have excellent health and medicinal benefits which deserve to be further explored.

Conclusions

Based on in vitro and in vivo testing, custard apple fruit have potent anti-diabetic, anti-obese, anti-microbial and anti-cancer properties.  Extensive human clinical trials need to be conducted to determine the efficacy and safety of the specific chemicals in custard apple fruit as anti-diabetic and anti-cancer agents.  Compared with other fruits, custard apple could be classed as one of the new superfruits.


References

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Disclaimer

Information in this review is presented for educational purposes only and should not be viewed as a recommendation for treatment of medical conditions or use of products mentioned in the review.

The review provides an overall perspective on the findings of medicinal research for custard apples.  It is not an exhaustive treatise.  The aims of this review are to collate current evidence and to stimulate further research.

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