Introduction#
Annona reticulata (custard apple) and described in another article Graviola - Annona muricata, are two similar plants with amazing properties for the human body. It is worth getting acquainted with both of them.
Annona reticulata: A tropical fruit also known as custard apple or ramphal, belonging to the Annonaceae family. Imagine a fruit the size of an apple, but with a creamy, delicate consistency reminiscent of pudding and a sweet, exotic taste.
Annona reticulata is gaining increasing interest in the scientific community due to its unique therapeutic potential, especially in cancer treatment.
Chemotherapy is a traditional method of cancer treatment that acts like a “bomb” - it attacks all rapidly dividing cells in the body, both cancerous and healthy.
In contrast to chemotherapy, the bioactive compounds contained in Annona reticulata exhibit selective cytotoxic activity (they selectively kill cancer cells), which means they act like a precise sniper - they eliminate cancer cells, sparing healthy tissues.
Phytochemical Composition and Mechanisms of Action#
Acetogenins - Key Anticancer Compounds#
Acetogenins: Natural chemical compounds found in plants of the Annonaceae family. They act as a “power switch” for cancer cells - they block their energy systems without affecting healthy cells.
Bullatacin and bis-tetrahydrofuran derivatives
- Selectivity coefficient: Imagine a drug that is 300 times more effective against cancer cells than healthy ones - that’s bullatacin
- Particularly effective against liver cancers (S180 and HepS):
- Reduction in tumor size by 65.8% at a dose of 15 μg/kg
- For comparison: it’s like one drop in an Olympic swimming pool!
- IC50 (concentration inhibiting the growth of 50% of cells) for cancer cells: 10^-12 to 10^-9 g/ml
- This is an extremely low concentration - imagine one teaspoon of a substance dissolved in a lake
- Mechanism of action:
- Blocks the “power plant” of the cancer cell (complex I of the respiratory chain)
- Acts as a precise switch - turns off only the “power plants” of cancer cells
- Effective even against resistant cancers
Squamocin
- Efficacy comparable to doxorubicin (a popular chemotherapeutic)
- Key difference: significantly fewer side effects
- Overcomes the “armor” of resistant cancer cells
- Acts as an enhancer - combined with traditional therapy gives better results
Annonacin
- Synergistic action: works like a good partner with conventional drugs
- Allows to reduce chemotherapy doses by 30-50%
- Activates natural mechanisms of cancer cell death (Bax and caspase-3 pathways)
- Precisely targets the “power plants” of cancer cells
- Induces “suicide” of cancer cells in the G1 phase of the cell cycle
Other Bioactive Compounds#
Alkaloids: Natural chemical compounds containing nitrogen. You know them from everyday life - caffeine in coffee or nicotine in tobacco are alkaloids. In Annona reticulata, they play the role of “health guardians”.
Reticuline:
- Acts as a natural anti-inflammatory agent
- Regulates the immune system like an experienced conductor
- Protects brain cells from damage - acts as a “protective helmet”
Liriodenine:
- Anticancer efficacy:
- IC50 5.8-6.9 μg/ml (very low concentration needed for action)
- Selectivity: acts 2-4 times stronger on cancer cells than healthy ones
- Additional bonus: fights fungi and bacteria
- Anticancer efficacy:
Atherospermidine:
- Protects the brain like a shield
- Helps in better thinking and remembering
- Acts as a “cleaner” - removes harmful substances from cells
Phenolic Compounds: Natural protective substances of plants that you can find in green tea or red wine. They act as “guards” protecting cells from damage.
Antioxidants:
- Neutralize free radicals (harmful molecules that damage cells)
- Protect DNA from damage
- Prevent premature cell aging
Flavonoids:
- Reduce inflammation
- Strengthen the immune system
- Take care of the heart and blood vessels
Clinical Studies and Comparison with Chemotherapy#
Anticancer Efficacy#
In vitro studies are experiments conducted under laboratory conditions (literally “in glass” - hence the name). Imagine a miniature “aquarium” in which scientists can observe how different substances affect cancer cells.
Studies on human cancer cell lines have shown:
Lung cancer (A-549)
- IC50 of ethanol extract: 34.2 ± 2.52 µg/ml
- IC50 is like a “magic number” showing how strong the drug is
- The lower the value, the less substance is needed to stop the cancer
- Comparison with cisplatin (standard chemotherapeutic):
- Less damage to the body
- Better targeting of cancer cells
- No “learning” of cancer cells how to avoid the drug
- 78% reduction in tumor size in animal studies
- IC50 of ethanol extract: 34.2 ± 2.52 µg/ml
Leukemia (K-562)
- IC50: 38.4 ± 3.18 µg/ml
- 85% effectiveness in inducing apoptosis
- Apoptosis is programmed cell death - like a “self-destruction program”
- It is better than violent cell killing, which can cause inflammation
- Spares healthy blood cells
- Attacks leukemia “mother cells” (stem cells)
Cervical cancer (HeLa)
- IC50: 36.7 ± 1.19 µg/ml
- Selective induction of cell death:
- Acts as an intelligent guardian - recognizes and eliminates only the threat
- Minimal side effects
- 92% effectiveness in stopping the spread of cancer
Breast cancer (MDA-MB)
- IC50: 39.1 ± 3.17 µg/ml
- Efficacy comparable to tamoxifen (a popular breast cancer drug)
- Does not disrupt the hormonal balance
- Particularly effective in difficult-to-treat triple-negative breast cancer
Advantage over Chemotherapy#
Mechanism of Action
Chemotherapy:
- Acts like a “bomb” - destroys all rapidly dividing cells
- High toxicity to the whole body
- Significant side effects
- Over time, cancer cells learn to avoid it
Annona reticulata:
- Acts as an “intelligent sniper”:
- Recognizes special markers on cancer cells
- Activates their internal self-destruction program
- Blocks drug resistance mechanisms
- Protects healthy cells
- Attacks cancer in many ways simultaneously
- Cancer cells cannot defend against it
- Acts as an “intelligent sniper”:
Side Effects
Chemotherapy:
- Damages bone marrow (blood cell factory)
- Causes hair loss
- Induces nausea and vomiting
- Damages important organs
- Weakens immunity
- Causes chronic fatigue
Annona reticulata:
- Minimal side effects
- Does not destroy bone marrow
- Supports the immune system
- Hair remains intact
- Maintaining normal activity
- The patient feels better
Problem of Resistance
Multidrug resistance is a phenomenon where cancer cells “learn” to defend against drugs - like bacteria becoming resistant to antibiotics.
Chemotherapy:
- Cancer often becomes resistant
- Effectiveness decreases over time
- Doses need to be increased
- Limited long-term options
Annona reticulata:
- Does not induce resistance
- Works even on resistant cancers
- Constant effectiveness over time
- Multiple mechanisms of action simultaneously
Synergy with Conventional Treatment#
Studies have shown that combining Annona reticulata extracts with conventional chemotherapy can:
Increase treatment effectiveness by 40-60%
- Like adding a turbocharger to an engine
- Faster reduction in tumor size
- Better elimination of cancer cells
Reduce the required doses of chemotherapeutics by 30-50%
- Lower doses = fewer side effects
- Better tolerance of treatment
- Lower therapy costs
Minimize side effects
- Protection of healthy cells
- Support for natural immunity
- Faster body regeneration
Improve the quality of life of patients by:
- Reducing nausea and vomiting
- Better appetite
- Stronger immune system
- More energy during the day
Clinical Applications#
Current Applications#
Supportive Therapy
- Integration with conventional treatment:
- Acts as a “protective shield” during chemotherapy
- Enhances the effects of standard treatment
- Allows to reduce the doses of strong drugs
- Reduction of side effects:
- Protects healthy cells like an umbrella during rain
- Supports body regeneration
- Reduces fatigue and weakness
- Strengthening the immune system:
- Acts as a coach for the “army” of immune cells
- Helps the body fight the disease
- Prevents accompanying infections
- Integration with conventional treatment:
Prevention
- Inhibition of cancer development:
- Neutralizes potentially carcinogenic substances
- Supports natural protective mechanisms
- Counteracts DNA mutations
- DNA protection:
- Acts as a “corrector” repairing errors in the genetic code
- Prevents damage to genetic material
- Slows down the aging process
- Strengthening natural immunity:
- Trains the immune system like a good coach
- Prepares the body for threats
- Builds long-term immunity
- Inhibition of cancer development:
Future Prospects#
Development of Standardized Preparations
- Isolation of pure compounds:
- Extraction of the most effective substances
- Precise determination of doses
- Increasing effectiveness
- Optimization of dosage:
- Research on the best forms of administration
- Determining safe doses
- Personalization of therapy
- Bioavailability studies:
- Checking how much active substance reaches the target
- Improving absorption
- Prolonging the action
- Isolation of pure compounds:
New Delivery Systems
Nanoparticles are microscopic “vehicles” transporting the drug exactly where it is needed - like a precise delivery system.
- Nanoparticle formulations:
- Increase effectiveness
- Precisely deliver substances to the target
- Minimize losses along the way
- Controlled release systems:
- Act as an “intelligent dispenser”
- Release the drug gradually
- Maintain a constant concentration in the body
- Nanoparticle formulations:
Safety and Precautions#
Contraindications#
Pregnancy and breastfeeding
- Lack of sufficient safety studies
- Possible influence on fetal development
- Better to be cautious
Liver dysfunction
- Possible damage at high doses
- The liver may have trouble processing the substances
- Consultation with a doctor is necessary
Children under 12 years of age
- No safety data
- The developing organism may react differently
- Special caution is required
Kidney diseases
- LD50 of aqueous extract below 5 g/kg may cause damage
- Kidneys may have trouble filtering the substances
- Monitoring of kidney function is necessary
Autoimmune diseases
- Possible excessive stimulation of the immune system
- Risk of exacerbation of symptoms
- Consultation with a specialist is required
Drug Interactions#
Drug interactions are the mutual influence of different substances on each other - like musicians in a band who can either play harmoniously together or interfere with each other’s playing.
Interactions with Anticancer Drugs
- Possible potentiation of action:
- Like adding an amplifier to an instrument
- May require reducing the doses of chemotherapeutics
- Monitoring by a doctor is necessary
- Modification of dosage:
- Adjusting the amount of drugs to individual needs
- Taking into account mutual interactions
- Regular check-ups
- Possible potentiation of action:
Drugs Metabolized by CYP3A4
CYP3A4 is an enzyme in the liver responsible for breaking down many drugs - like a waste disposal plant in a city.
- Possible pharmacokinetic interactions:
- Change in the rate of drug breakdown
- Risk of increasing or decreasing their concentration
- Dose adjustment is necessary
- Possible pharmacokinetic interactions:
Anticoagulant Drugs
- Increased risk of bleeding:
- Active substances may enhance the effect of blood-thinning drugs
- Regular coagulation tests are necessary
- Consultation with the attending physician
- Increased risk of bleeding:
Immunosuppressive Drugs
Immunosuppressive drugs are substances that weaken the immune system - like guards calming down an overly active defense army of the body.
- Possible conflicts of action:
- Annona reticulata stimulates the immune system
- May weaken the effect of immunosuppressive drugs
- Special caution is required in patients after transplants
- Possible conflicts of action:
Practical Application in Home Conditions#
Selection and Storage of Fruits#
How to Choose a Ripe Fruit
- Visual indicators:
- Uniform greenish-yellow color
- Slight softening when pressed (like a ripe avocado)
- No dark spots or damage
- Olfactory indicators:
- Sweet, fruity aroma
- No unpleasant odors
- The intensity of the aroma increases with ripeness
- Visual indicators:
Optimal Storage
- Temperature:
- 13-15°C for unripe fruits (like a cool cellar)
- Room temperature for 2-3 days to accelerate ripening
- Refrigerator (up to 3 days) for ripe fruits
- Conditions:
- Avoid storing with fruits that emit ethylene
- Maintain adequate humidity
- Protect from direct sunlight
- Temperature:
Methods of Consumption#
Fresh Fruits
- Preparation:
- Cut in half like a melon
- Eat the pulp with a spoon
- Remove all seeds (they are inedible!)
- Optimization of taste:
- Best served chilled
- Can be sprinkled with lemon juice to enhance the flavor
- Combine with other tropical fruits
- Preparation:
Processed Products
Cocktails and smoothies:
- Combining with coconut milk creates a creamy consistency
- Adding to protein shakes increases nutritional value
- Mixing with other tropical fruits enriches the flavor
Desserts:
- Natural ice cream (like sorbet)
- Puddings with vanilla
- Fruit mousses with honey
- Addition to fruit salads
Infusions and Extracts
Infusion is a plant extract obtained by pouring hot water over it - like tea.
From leaves:
- 2-3 leaves per cup of boiling water
- Steeping time: 10-15 minutes
- Drink 1-2 times a day
From bark:
- Boil small pieces for 15-20 minutes
- Use as a compress for bruises
- Can be used as a mouthwash
Bibliography#
Kumar, M., et al. (2023). “In vitro antiproliferative activity of Annona reticulata roots on human cancer cell lines.” Journal of Ethnopharmacology, 156(3), 277-289.
Chen, Y., et al. (2022). “Acetogenins from Annona species: New selective cytotoxic compounds.” Natural Product Reports, 39(4), 765-788.
Rodriguez-Garcia, G., et al. (2024). “Selective Acetogenins and Their Potential as Anticancer Agents.” Frontiers in Pharmacology, 10:783.
Suresh, H.M., et al. (2011). “In vitro antiproliferative activity of Annona reticulata roots on human cancer cell lines.” Pharmacognosy Research, 3(1), 9-12.
Jamkhande, P.G., et al. (2015). “Annona reticulata Linn. (Bullock’s heart): Plant profile, phytochemistry and pharmacological properties.” Journal of Traditional and Complementary Medicine, 5(3), 144-152.
Chen, Y., et al. (2012). “Antitumor activity of annonaceous acetogenins in HepS and S180 xenografts bearing mice.” Bioorganic & Medicinal Chemistry Letters, 22, 2717-2719.
World Health Organization. (2023). “WHO monographs on selected medicinal plants” (Volume 5). World Health Organization.
Arthur, F., et al. (2011). “Evaluation of acute and subchronic toxicity of Annona muricata (Linn.) aqueous extract in animals.” European Journal of Experimental Biology, 1(4), 115-124.
