Phytochemical Properties and Therapeutic Applications of Annona muricata: A Comprehensive Review

Many plant species act as miniature chemical factories, producing an array of secondary metabolites, including phenolic and polyphenol compounds, terpenoids, essential oils, alkaloids, tannins, saponins and coumarins.¹ Annona muricata often referred to as graviola, soursop, or guanabana, displays a range of roles in the medicinal properties of plants. The tree has a thin appearance and low branches and its fruit is known for its irregular, heart-shaped appearance and contains creamy white parenchyma cells encapsulated by skin with delicate, curving spines. A. muricata finds extensive use in traditional medicine for various infections and diseases, including fever, acne, insomnia, hypertension, rheumatism, respiratory disorders, parasitic and bacterial infections, inflammation, diabetes, malaria, kidney and liver problems, as well as soothing and anticancer.² The plant’s seeds treat parasitic infections; its fruits address arthritis, diarrhea and nervous disorders, while its leaves, rich in bioactive compounds, are utilized for headaches, insomnia, cystitis and cancer treatment.³ The scientific community has recognized the significance of phytochemicals from plants in pharmaceutical discoveries, highlighting the therapeutic potential of natural products (Figure 1). However, despite scientific interest, only a restricted number of comprehensive scientific examinations of plant species are essential to fully understand the physiological impacts of these plants and their phytochemical compounds. A. muricata, with its rich ethnomedicinal history, presents a promising avenue for pharmaceutical exploration, as described in this review covering its botany, distribution, ethnomedicinal uses, phytochemistry, biological activities and potential mechanisms.⁴ Throughout history, medicinal plants have been critical in maintaining human well-being. A. muricata is indigenous to Central and South America and the Caribbean region. Its rich ethnomedicinal history and extensive traditional use make it a valuable candidate for further research into its potential therapeutic applications.⁵ The active ingredients of plants have garnered significant scientific interest for their potential in agriculture and medicine, leading to an exploration of their biological activities.⁶ However, our understanding about the detailed scientific examination of a range of plants of some species is limited, hindering our ability to understand their inherent role treatments fully. A. muricata is the scientific name for a plant species also referred to as Graviola Soursop or Gunbanana and it originates from a tropical region. The plant is indigenous to Central and South America and the Caribbean region. Its rich ethnomedicinal history and extensive traditional use make it a valuable candidate for further research into its potential therapeutic applications. Understanding the biological activities and mechanisms of action of A. This review aims to provide a detailed analysis of the plant taxonomy, geographical range and traditional medicinal use of A. muricata while also summarizing its chemical composition, biological effects and potential modes of action.

Graviola-coracao (Portuguese)

Corossolier (French)

Zi guo lao (Chinese)

Guyabano (Filipino)

Toge-banreisi (Japanese)

Gang (Vietnamese)

Mullaatha (Tamil)

Mullatha (Malayalam)

Hanuman Phala (Hindi)

Ramphal (some regions of India)

Laxmanphal (certain parts of India)

Hanuman Phal (also used in some regions)

Mullachakka (Kerala)

Mullu Seetha (Tamil Nadu)

Soursop (English-speaking countries)

Graviola (Brazil and other Portuguese-speaking regions)

Guanábana (Mexico, Colombia and Puerto Rico)

Corossol (French-speaking regions like Haiti and parts of Africa)

Stachelannone (in German-speaking regions)

Jaboticaba (in some parts of South America)

Zuurzak (in Dutch-speaking areas, including Suriname and the Netherlands Antilles)

Taxonomy (family, species)

Order: Magnoliales

Family: Annonaceae Juss.-Custard-apple family

Genus: Annona L.-annona

Species: Annona muricata L.-soursop

Super division: Spermatophyta-Seed plants

Division: Magnoliophyta-Flowering plants

Class: Magnoliopsida-Dicotyledons

Subclass: Magnoliidae⁷

A. muricata, sometimes called Soursop or Graviola, is a tropical shrub highly valued for its fruit. The plant offers both therapeutic advantages and possible adverse effects.⁸ This plant belongs to the Annonaceae family and is categorized under the Magnoliales order and Magnoliophyta division. Annona has more than 70 species, with A. muricata being the most widely cultivated. Soursop trees often attain a height of 5-10 m and a diameter of 15-83 cm. They have a unique look due to their low branches. They exhibit continuous flowering and fruiting throughout the year but are altitude-dependent and seasonal fluctuations may occur. They are native to tropical climates and produce visually appealing yellow-green blooms. The fruit is an oval berry, initially having a dull green hue and holds 55 to 170 seeds. These seeds are black while fresh, turn to light brown when mature and maintain the same color when dried. The white, creamy pulp has a distinctive fragrance and flavor, making it a highly valued component in tropical gastronomy. A. muricata, formerly indigenous to hot tropical regions in South and North America, has spread worldwide to tropical and subtropical locations, such as India, Malaysia and Nigeria. The tree yields sizable, heart-shaped, verdant fruits, about 15 to 20 cm in diameter, with more nutritional value. Although it is widely consumed as a meal, its medicinal capabilities have garnered significant interest, especially in traditional and herbal medicines. Moreover, it is important to exercise care since excessive ingestion of certain plant components may lead to toxicological consequences.

The A. muricata tree and other Annona species, such as A. squamosa and A. reticulata, are extensively used in traditional medicine to treat various health conditions.⁹ The fruit alleviates ailments such as arthritic pain, diarrhea and fever. Tropical Africa highly regards this plant for its astringent effects and its effectiveness as an insecticide. In India, the fruit and bloom have many uses in medicinal therapies, such as anti-inflammatory and anthelmintic effects.¹⁰ The plant’s leaves, bark and roots have diverse therapeutic properties. In addition to its therapeutic use, the fruits are utilized in various culinary recipes. The plant’s therapeutic properties are derived from various plant parts used traditionally for colds, influenza and malaria (Table 1).^11–20

Plants produce primary metabolites for their survival and secondary metabolites in response to environmental stimuli. These secondary metabolites offer diverse medicinal properties, including alkaloids, polyphenols, terpenoids, essential oils, coumarins, saponins and tannins. A. muricata, are renowned for their abundance of annonaceous Acetogenin compounds (AGEs). A. muricata fruit contains essential minerals, including potassium, calcium, sodium, copper, iron and magnesium, making it a valuable source of nutrients for human consumption.²¹

Alkaloids extracted from the root of A. muricata, include coclaurine, reticuline, argentininee, atherosperminine and xylopine have garnered interest for their potential cytotoxic effects on cancer cells. These alkaloids exhibit cytotoxicity against many cancer cell lines, including HL-60 (Human Leukemia), A549 (human lung adenocarcinoma) and HepG2 (liver cancer).²² Xylopine had the most significant cytotoxic effect, with an IC₅₀ value ranging from 20 to 80 μM, suggesting it is a cytotoxic agent against cancer cells.

The ethyl acetate A. muricata leaf fraction includes kaempferol-3-O-glucoside and 1-(4-Hydroxyphenyl)-3-P henylpropan-1-one, both of which have antioxidant activity.²³ The polyphenols derived from A. muricata, including kaempferol, procyanidins, catechin and quercetin, exhibit cytotoxic effects on HeLa cancer cells and 3T3 fibroblast cells.

A. muricata includes acetogenins such as annomuricin A, B and C, muricatocin C, cis-goniothalamicin, muricatacin, arianacin, annonacin-10-one, cis-annonacin and javoricin. These compounds include hydroxyl functional groups with alpha and beta-unsaturated gamma-lactone. Reported studies indicates that 15-acetyl guanacone has significant antioxidant properties by effectively scavenging DPPH and ABTS radicals. A high concentration of 10 μg/mL caused substantial harm to the genetic material of MCF-7 cells, a specific kind of human breast cancer cells.²⁴ Acetogenin suppresses the growth of colon cancer cells by facilitating the movement of Apoptosis-Inducing Factor (AIF) into the nucleus, therefore beginning cell death that is reliant on AIF. The expression of Bcl-2 and Mcl-1 proteins was suppressed in both SW620 (human colorectal cancer) and RKO (poorly differentiated colon carcinoma) cell lines both in laboratory settings and in living organisms.²⁵ Acetogenins retards the production of ATP in mitochondria, specifically in cancer cells. This restriction on ATP production is achieved by suppressing the activity of NADH: ubiquinone oxidoreductase, often known as Complex I, is a component of the mitochondrial electron transport system seen in cancer cells.

GC-MS study indicated that the oil consists mostly of sesquiterpenes, with β-caryophyllene being the predominant.²⁶ On the other hand, the leaf oil extracted from A. muricata in Vietnam includes β-pinene (20.6%), germacrene D (18.1%), ρ-mentha- 2,4(8)-diene (9.8%), α-pinene (9.4%) and β-element (9.1%). The main components of the leaf oil extracts are δ-cadinene, epi-α- cadinol and α-cadinol. The primary constituents of the essential oil derived from the fruit pulp consist of esters of aliphatic acids, with 2-hexenoic acid methyl ester and 2-hexenoic acid ethyl ester. Furthermore, the fruit pulp oil contains mono- and sesquiterpenes, such as β-caryophyllene, 1,8-cineole and linalool. Advanced Glycation End products (AGEs) are a distinct category of secondary metabolites called C-35/C37 molecules. These compounds are synthesized by the polyketide pathway using long-chain fatty acids (C-32/C34) (Figures 2, 3).²⁷

The Table 2 provides a comprehensive overview of the pharmacological activities associated with various parts of Annona muricata and its extract. Each part of the plant, including leaves, fruits, seeds, bark and roots, exhibits unique therapeutic activities, ranging from anticancer and antimicrobial to anti-inflammatory and antioxidant effects. This compilation highlights the potential of Annona muricata as a valuable resource in natural medicine and pharmaceutical research. Specific pharmacological activities are detailed below.

Figure 1:
A. muricata tree, leaves, flower, fruit, seed.⁶

Figure 2:
Bioactive metabolites present in A. Muricata.

An overabundance of Reactive Oxygen Species (ROS) inside the cells may result in oxidative stress, which disrupts metabolic processes and causes cell death due to biochemical and physiological harm.⁴⁴ Padma and her colleagues conducted a further experiment and found that the ethanolic extract derived from the stem bark of A. muricata showed adaptogenic characteristics. It decreased lipid peroxidation induced by cold immobilization stress in the brains and livers of rats.

A. muricata extracts possess antiviral activity against Herpes Simplex Virus (HSV), Human Immunodeficiency Virus (HIV) and influenza virus, which is attributed to acetogenins, alkaloids and flavonoids.⁴⁵ The antiviral mechanism involves inhibiting viral replication and attachment to host cells. Studies have shown that A. muricata extracts can disrupt viral entry and replication, thus preventing viral spread and infection.⁴⁶ Compounds isolated from A. muricata, such as annonacin, annonamine and quercetin, exhibit potent antiviral activity, targeting various stages of the viral life cycle. These compounds, including acetogenins, alkaloids and flavonoids, demonstrate broad-spectrum antiviral effects against HSV, HIV and influenza viruses. The results emphasize the capacity of A. muricata to serve as a reservoir of innovative antiviral substances.

The leaves of A. muricata are traditionally used in decoction form in numerous African regions to manage fever and convulsive seizures. This traditional practice has garnered interest in scientific research to substantiate its efficacy. The anticonvulsant effect of A. muricata leaves was reported for its ethanolic extract to counteract tonic-clonic seizures produced by pentylenetetrazol convulsions in rats.

Extensive in vivo studies have explored A. muricata’s traditional use in treating diabetes. There was a significant decrease in blood glucose levels from 21.64 to 4.22 mmol/L in an early reported study.⁴⁷ Similarly, research conducted in Cameroon examined the ethno pharmacological use of A. muricata leaves in diabetic rats induced by streptozotocin and revealed the encouraging antidiabetic benefits of the extract, which were related to its antioxidant and hypolipidemic activities. The histopathological study provided further confirmation for these observations, demonstrating the leaf extract had stimulated the regrowth of pancreatic β-cells.⁴⁸

A. muricata is also known for its traditional medicine, which alleviates arthritis. The plant extract was administered at various dosages (3, 10, 30 and 100 mg/kg) to Complete Freund’s Adjuvant (CFA) induced arthritic rats, which revealed a significant correlation between the dose of the extract and the amount of decrease in swelling within two weeks.⁴⁹ A. muricata leaves also inhibited the production of pro-inflammatory cytokines, such as TNF-α and IL-1β, crucial for joint destruction in arthritis which suggests that A. muricata leaves have anti-arthritic properties by suppressing these cytokines. The dose-dependent reduction in swelling and cytokine suppression indicates A. muricata’s potential as a natural remedy for arthritis.

When given orally at doses of 10, 30, 100 and 300 mg/kg, the leaf extracts of A. muricata in ethanol showed anti-inflammatory effects.⁵⁰ This intervention markedly decreased the inflammation caused by carrageenan in the paws of rats by 79%, with a direct correlation to the amount administered. This was associated with reductions in leukocyte movement and fluid secretion. The observed effect was linked to a reduction in the production of TNF-α and IL-1β in mice with arthritis caused by CFA and ear edema produced by xylene.

Protozoal diseases like leishmaniasis and trypanosomiasis are of global health concerns, posing significant treatment challenges due to increasing medication resistance and toxicity. In a study examining A. muricata, researchers found that the seeds contained two active compounds, annonacinone and corossolone, demonstrated significant efficacy against leishmania species. The anti-parasitic effects of these compounds were dose-dependent, indicating proper dosage is critical for maximizing efficacy while minimizing potential toxicity.⁵¹ The researchers noted that annonacinone and corossolone inhibited the growth of leishmania species, suggesting a potential mechanism involving the disruption of mitochondrial function.

Multiple studies have shown the inhibitory effects of different plant extracts on tumor cell development. Furthermore, scientific studies have examined the impact of isolated Advanced Glycation End products (AGEs) on several cancer cell lines.⁵² Only a limited number of researches have investigated the fundamental biochemical processes. The effects of an ethyl acetate extract of A. muricata on colon cancer cells (HT-29 and HCT-116) and lung cancer cells (A549) were examined. This extract triggered programmed cell death (apoptosis) and halted the progression of the cell cycle, mainly in the G1 phase. An aqueous extract inhibited BPH-1 cells and reduced rat prostate size.

Figure 3:
Structure of Phytoconstitiuents.

The incidence of pancreatic cancer is on the rise, largely because of the absence of first clinical signs. The powder derived from the leaves and stem extract of A. muricata has inhibitory effects on cell proliferation and tumor growth in subcutaneous xenograft models and pancreatic cancer cell lines. These effects result in the cessation of cell division, the initiation of programmed cell death” and the start of programmed cell death. A. muricata triggers metabolic catastrophe, modulates glucose metabolism to induce cell death and down-regulates MUC4 (mucin).⁵³

Lung cancer is a major contributor to global mortality from cancer. Studies have shown that the ethyl acetate extract is derived from the foliage of A. muricata. Exhibits cytotoxic effects on the A549 cell line, a human lung cancer variant. This extract induces cell cycle arrest, specifically in the G0/G1 phase and enhances apoptosis.⁵⁴

Multiple studies have demonstrated that extracts from the fruit pulp of A. muricata have antiproliferative properties in many cell lines, such as 22Rv1, LNCaP and PC-3. These extracts also inhibit NOX activity, a mechanism linked to downregulating HIF-1 expression.⁵⁵

Among women, breast cancer is the most widespread cancer. While early stages are treatable, advanced cases pose challenges. Recent studies demonstrate A. muricata’s potent antiproliferative and anticancer effects. Cancer cells exposed to A. muricata’s ethyl acetate extract exhibit apoptosis-like changes, including cell membrane rupture.⁵⁶

A. muricata leaf extract demonstrates anticancer properties, particularly in Colorectal Carcinoma (CRC). It increases the protein caspase-3, which promotes programmed cell death (apoptosis), inhibits the movement and infiltration of HT-29 and HCT-116 cell lines, the initiation of cell cycle arrest and cell death results in the destabilization of the mitochondrial membrane, affecting the function of Bax and Bcl-2 proteins.⁵⁷?

Most tumors that impact the head and neck area region, often called head and neck squamous cell carcinomas; occur in the mouth and throat. A. muricata leaf extract demonstrates antiproliferative effects and arrests cell cycle during the G2/M phase. Combining A. muricata extracts with cisplatin may enhance effectiveness due to their apoptosis-inducing properties.⁵⁸

The ethanol and methanol extracts obtained from A. muricata leaves have been found to trigger apoptosis, a process of programmed cell death, in different forms of leukemia, including the cell lines of human myelogenous leukemia (K562), human T-cell leukemia (CCRF-CEM), multidrug-resistant leukemia (CEM/ADR5000), B-cell chronic lymphocytic leukemia, myeloid leukemia and multiple myeloma.⁵⁹

Methanol, extract derived from the foliage of Annona muricata, has inhibitory effects on the rapid increase in the number of Hep-2 (laryngeal carcinoma) cell lines.⁶⁰

In conclusion, A. muricata is valued for its rich composition of essential vitamins such as thiamine, niacin and Vitamin C, as well as minerals including calcium, magnesium, potassium, iron, phosphorus and zinc. Its abundance of acetogenins, which are long-chain fatty acid moieties, has been detected in many plant components, with the highest concentrations found in the seeds. Moreover, the leaves of A. muricata contain corossolone, p-coumaric acid, epicatechin, epicatechin gallate and ferulic acid, among other phytoconstituents which contribute to the plant’s diverse medicinal applications, including antioxidant, anti-inflammatory, antiparasitic, antidiabetic, antibacterial, anticancer, wound healing, antiulcer, anti-malarial, antihypertensive and gastroprotective activities.

I express my gratitude to Dr. J Vimalin Hena, the Associate Professor of the Department, for providing all the required inputs on time and Dr. Sajan Kurian, the Dean of the Department of Agriculture and Biosciences, for his support in seeing this work through to completion.