Annona muricata and Its Anticancer Activity: Comparison
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Annona muricata is a member of the family Annonaceae and is familiar for its medicinal properties. A. muricata has been identified to have promising compounds that could potentially be utilized for the treatment of cancer. The most prevalent phytochemical components identified and isolated from this plant are alkaloids, phenols, and acetogenins.

  • Annona muricata
  • ethnomedicinal
  • bioactive metabolites
  • pharmacological activities
  • anticancer activity

1. Introduction

Cancer is the world’s most prevalent cause of death, accounting for roughly 10 million fatalities in 2020 [1] and approximately 400,000 children are diagnosed with cancer annually [2]. As reported by the International Agency for Research on Cancer (IARC), there were 17.0 million new cases of cancer in 2018. By 2040, population growth and aging are expected to increase the global cancer burden to 27.5 million new cases and 16.3 million deaths from cancer [3]. Despite these challenges, the estimated future cancer burden is likely to be much higher due to the acceptance of lifestyles linked to cancer risk. Lung, liver, stomach, colorectal, prostate, breast, and cervical/uterine cancer are probably the most frequently diagnosed cancers recorded in economically developing countries. Medical breakthroughs to treat and prevent this disease are always in demand [4,5[4][5][6],6], and attention toward plant-derived compounds reduces the risk of side effects compared to current chemotherapy treatments. Drug resistance, and notably multidrug resistance (MDR), whose ultimate consequence is apoptosis resistance, has long been regarded as the most significant barrier in cancer therapy. Natural products with multiple potential targets may aid in the restoration and maintenance of signaling network resilience. Consequently, natural products may be utilized to prevent or treat drug resistance in cancer treatment by boosting the intracellular concentrations of chemotherapeutic drugs by controlling MDR or activating alternative nonapoptotic cell death pathways, such as necroptosis, autophagy, and oncosis [7]. Due to their demonstrated safety, low cost, and oral bioavailability, dietary phytochemicals have several advantages over synthetic pharmaceuticals [8]. Plants have been used to treat various diseases since antiquity [9]. According to the World Health Organization (WHO), approximately 80% of the global population relies on traditional medicines, plant extracts, or plant-based substances for primary healthcare [10]. From the 1940s until the end of 2014, natural compounds or modified natural products accounted for 49% of the 175 small molecules authorized for cancer treatment [11,12][11][12]. According to the most recent information, of the 1881 approved medicinal entities over nearly four decades from 1981 to 2019, over 23% were derived from natural sources, i.e., unaltered natural products (N; 3.8%), botanical drugs (NB; 0.8%), or natural product derivatives (ND; 18.8%) [13]. An estimated 25% of the 247 newly approved anti-cancer drugs were derived from natural products [13].
Herbal medicine is a global icon of alternative medicines in most significant fields. Medical plant research is very much needed to promote the appropriate use of herbal medicine and to assess its potential to be developed as new drugs [14]. Plants with medicinal properties have been utilized to cure various ailments since before the dawn of history. Several references to medicinal plants and their disease-preventive properties are documented in ancient texts [15,16,17][15][16][17]. The key features were the chemical compounds of medicinal plants that can exert a physiological effect on the human system [18]. The secondary metabolites and bioactive compounds present in various medicinal plants have been studied and found to have anti-cancer effects [19]. Most of these natural substances exert their anticancer characteristics to restrict the initiation, development, and progression of cancer by influencing cellular proliferation, differentiation, apoptosis, angiogenesis, and metastasis [20]. Annona muricata (also known as graviola) extracts are among a plethora of botanical compounds that have demonstrated potential therapeutic efficacy and all of this plant’s aerial parts are utilized as natural medicines [21,22][21][22]. There have been reports of widespread use of A. muricata by people with cancer in numerous places throughout the globe [22]. In a Jamaican study on the opinions of cancer patients regarding using medicinal plants for self-medication, 60% of participants disclosed using A. muricata for the treatment of various malignancies, especially breast and prostate cancer [23]. Similarly, 80.9% of patients with breast, prostate, or colorectal cancer have been reported to use A. muricata in specialty oncology clinics in Trinidad [24]. Furthermore, a cross-sectional study suggests that 14% of Peruvian patients with liver cancer have used A. muricata to treat their cancer-related symptoms [25]. Similar claims of prostate cancer chemopreventive polyphenols in Nigerian foods containing A. muricata have been reported [26]. While the use of A. muricata leaf for cancer therapy has been reported in the Philippines [27] and Peru [28], it was reported to be utilized for gastric cancer therapy in Mexico [29].

2. Botanical Description and Distribution

The Annonaceae family includes about 130 genera and 2300 species, including A. muricata L., also known as soursop, graviola, guanabana, pawpaw, and sirsak [30,31][30][31]. A. muricata is native to the warmest tropical areas of South and North America, but now it has spread across the world’s tropical and subtropical countries, including India, Malaysia, Nigeria, Australia, and Africa [32]. Evergreen, terrestrial tree A. muricata grows to a height of 5 to 8 m with a broad, glossy, dark green, open, and round canopy. Individual yellow flowers on woody stalks are larger on this tree. The edible fruits of the tree are large, oval, or heart-shaped, green in color with more than 4 kg weight, with a diameter of 15 to 20 cm. The white juicy fibrous segments that make up the fruit pulp form an elongated receptacle. Fruit may have 5–200 seeds [33]. The skin is reticulated and has short spines, making it look leathery. It has a creamy, granular inner surface that easily separates from the soft pithy base [28].

3. Bioactive Metabolites Responsible for Various Pharmacological Activities in A. muricata

Phytochemicals are constitutive metabolites produced by the primary or secondary metabolism of various parts of plants and have important plant functions (Figure 1). Plant growth and metabolism are also influenced by primary and secondary metabolites [34].
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Figure 1.
Diagram depicting the role of Phytochemicals (
a
) and bioactive metabolites present in
Annona muricata
(
b
).
Alkaloids [35], megastigmanes, flavonol triglycosides [36], phenolics, cyclopeptides, and essential oils have all been found in various parts of the A. muricata (Figure 1). Despite this, Annona species, including A. muricata, are a good source of reported acetogenin (AGE) compounds. The presence of multiple major minerals in the A. muricata fruit, such as potassium, calcium, sodium, copper, iron, and magnesium, indicates that daily consumption of the A. muricata fruit will aid in the supply of vital nutrients and components to the human body [37].

4. Ethnomedicinal Uses

Due to their therapeutic potential, the Annonaceae family has been widely investigated in recent years. The medicinal uses of the Annonaceae family have been recorded for a long time, and this species has gained attention in recent years due to its bioactivity and traditional uses [50][38]. Medicinal herbs are widely recognized as the foundation for human life and health care. Chronic degenerative diseases have attained widespread levels and are now regarded as serious health problems; as a result, treatment of these diseases is given clinical priority [68][39]. A. muricata has been proposed as an insecticide [69][40] and a parasiticide [70][41] in ethnobotanical studies. Fever [70][41], sedative [71][42], respiratory disease [70][41], malaria [72[43][44],73], gastrointestinal disorders, liver, heart, and kidney disorders [74,75,76][45][46][47] have all been treated with fruit juice and leaf/branch infusions. In recent years, this has been widely used for hypoglycemic [42][48], hypotensive [70][41], and cancer treatments [77,78][49][50] (Table 1).
Table 1.
Ethnomedical uses of
A. muricata
.

Ethnomedicinal Uses

Plant Parts Used

Graviola Extract/Chemical Compound

References

Insecticide

Seed, leaves, barks, stems, roots and flowers

Acetogenins

[79,80][51][52]

Parasiticide

Leaf

Ethanolic extract and its fractions, methanol extracts, and acetogenins, ethyl acetate extract

[81,82,83,84][53][54][55][56]

Hypotensive

Leaf, fruit

Aqueous extract,

the alkaloids, isoquinoline, coreximine, and anomurine

[85][57]

Fever

Leaf

Flavonoids

[70,86][41][58]

Respiratory illness

Leaf

Essential Oil

[47,70][41][59]

Sedative

Leaf

Hydroalcoholic extract

[87][60]

Malaria

Seed, leaf

Ethanolic extract

[50,88][38][61]

Gastrointestinal disorders

Leaf

Ethyl acetate extract

[70,89][41][62]

Liver, heart, and renal disorders

Fruit, Leaf

Ethyl acetate and ethanol extracts

[50,89,90,91,92,93][38][62][63][64][65][66]

Hypoglycemic

Leaf, branch

Ethanolic extract

[91,94,95][64][67][68]

Cancer

Leaf, fruit, stem, bark and branch

Annonaceous acetogenins, alkaloids, flavonoids, sterols, and others

Discussed in detail in the following sections
The leaves [96[69][70][71][72][73],97,98,99,100], pericarp [36[36][74],101], fruits [34[34][75],102], seeds [36,103][36][76], and roots [35] of A. muricata have ethnomedical uses. Roots of A. muricata have been employed in herbal therapy, whereas stem barks, stems, seeds, and leaves are the most common constituents in traditional medicinal decoctions [104,105,106][77][78][79]. In A. muricata extracts, Coria-Téllez et al. [70][41] found 212 bioactive chemicals. Traditional medicine uses different plant parts to cure a range of diseases and ailments, including inflammation [77][49], rheumatism, diabetes [42][48], hypertension [107][80], and parasite infestation [82][54]. The fruit is often used to treat arthritis and fever, whereas the seed is used to treat worms. Parasitic diseases can be handled with seeds and fruits as well. The leaves are also used as a traditional medicine for treating collapses [108][81], hypoglycemia, inflammation, and spasm relief treatment [30]. Furthermore, the plant’s leaf has been nicknamed “the cancer killer” and is often used in conventional cancer care medicine, as the name suggests [91,109][64][82]. It is well known that the plant was widely used as a source of chemically active metabolites due to its various curative properties [109][82].

5. Role of Annona muricata against Various Types of Cancer

5.1. Pancreatic Cancer

Pancreatic cancer, the deadliest malignancy in the world and the 4th largest source of malignancy fatalities, seems to have a 5-year survival rate of only 8% [110][83]. Due to a lack of early clinical symptoms, there is a high mortality rate in late diagnosed patients. Late diagnosis, resistance to available chemotherapy treatments, and cancer’s high aggressive behavior have encouraged new early detection markers, as well as research and evolution of chemo-preventive and chemotherapy agents. Even though several plant chemicals have been studied for pancreatic cancer treatment, none have yet been scientifically proven [111][84]. A. muricata capsules containing leaf and stem powder have anti-proliferative and antitumor effects in pancreatic cancer cell lines (IC50 values were 200 µg/mL in FG/COLO357 and 73 µg/mL in CD18/HPAF), and in subcutaneous xenografts, these activities included inducing cell cycle arrest with apoptosis. The migratory capacity of pancreatic cells has been similarly diminished upon treatment with the extract at a concentration of 100 µg/mL by a transwell assay [112][85]. Similar anti-proliferative effects have been identified for the hexane fraction of A. muricata leaves against pancreatic cancer cell line, Capan-1 (IC25 values were 7.8–8 μg/mL), which is rich in flavonoids [113][86]. A. muricata also inhibited the motility and invasion of PC cells by downregulating the mucin MUC4 (Figure 2) [114][87]. Despite MUC4′s enormous pathological importance in various cancers, A. muricata’s high therapeutic suitability for various tumors, especially PC, is indicated by MUC4 down-regulation. A. muricata, in addition to downregulating MUC4, has been shown to cause cell death by modifying glucose metabolism and inducing metabolic catastrophe [112,115][85][88].
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Figure 2.
Representation of the role of MUC4 in pancreatic cancer (
a
) and action of graviola extract against lung cancer (
b
).
Recently, anticancer strategies targeting cancer cells’ metabolism have received considerable attention. Tumor cells need inexorably more energy to proliferate, which is obtained from glycolysis. Recent research suggests that KRAS controls glycolysis by upregulation of the expression of GLUT1 in conjunction with HK1, HK2, PFKl, and LDHA [116][89]. When inhibiting KRAS, decreased cellular metabolism has been associated with anticancer effects [117][90]. To achieve this anti-proliferative effect, it may be necessary to modify glucose levels by lowering glucose uptake or altering GLUT expression. The metabolic catastrophe caused by A. muricata, which was triggered by the downregulation of HIF-1, GLUT1, GLUT4, HK2, and LDHA in PC (prostate cancer) cells, was associated with decreased glucose absorption and ATP generation [112][85]. Bullatacin-type of acetogenin promotes cytotoxic effects by regulating metabolic processes and suppressing the mitochondrial complex I proton pumping mechanism, which inhibits ATP generation and NADH oxidation [115][88]. The components in the A. muricata extract suppress signaling pathways involved in PC cell formation, proliferation, and metabolism. The cytotoxicity of A. muricata in cancer cells has prompted scientists to investigate deeper into the molecular mechanisms behind these results. According to Torres [112][85], the activation of ERK and PI3K pathways plays a critical role in pancreatic cancer cell survival, and inhibiting these pathways contributes to pancreatic cell growth inhibitors. In a similar study, pancreatic cells treated with A. muricata extracts reduced the ERK and Akt pathways activation. As a result, the reduced viability of pancreatic cells administered with plant extract [112][85] is consistent with the inhibition of these pathways. A. muricata was also found to be inhibited by metastasis. Torres’ research on pancreatic cells showed that after treatment with an A. muricata extract, pancreatic cancer cells’ migratory capacity was reduced, as measured by a transwell assay, implying that herbal extract reduces pancreatic cancer cell motility. The cortical actin and microtubule network composition influences cancer cell motility and migration. Furthermore, cellular ATP depletion has been linked to cytoskeleton actin reorganization and a suspension of microtubule dynamics, which are thought to cause mitotic arrest. A. muricata extracts disrupt the cortical actin network, stopping cancer cells from moving around [112][85].

5.2. Lung Carcinoma

Lung cancer is the most common cancer-related death worldwide [110][83]. Because of chemotherapeutic tolerance, many patients with lung cancer succumb to the disease. In vitro studies of A549 (human lung adenocarcinoma) cell lines revealed that A. muricata leaf extract possesses cytotoxic activity and the IC50 values for hexane, ethyl acetate, and methanol extracts were 21.05 ± 0.42 µg/mL, 5.09 ± 0.4 µg/mL and ≥ 100 µg/mL respectively, caused cell cycle arrest at the G0/G1 phase and apoptosis (Figure 2) [121][91]. cis-Annonacin-A-one and trans-Annonacin-A-one, cis- gigantetrocinone and trans-gigantetrocinone, cis-isoAnnonacin and trans-isoAnnonacin and squamolone isolated acetogenins possess cytotoxic activity against A549 cell lines, and the ED50 values were 3.39 × 10−2, 9.74 × 10−3, 4.42 × 10−5, ≥ 10, 1.48 × 10−3, respectively [122][92]. A. muricata leaf ethyl acetate extract (AMEAE) possesses a cytotoxic effect on the A549 cell line, and the IC50 value was 5.09 ±  0.41 μg/mL after 72 h of treatment, inducing apoptosis. This was proved by multiple high-content screening cytotoxicity studies. The results showed that A549 cells treated with the A. muricata extract inhibited growth potential, and their apoptosis pathway was upregulated [121][91]. Graviola extract inhibits nuclear factor-κB (NF-κB) signaling, increases ROS production, and enhances the Bax/Bcl-2 ratio–mediated inhibition of mitochondrial membrane potential, activation of cytosolic cytochrome c, and caspase-3/9 as reported in A549 cell line [121][91].

5.3. Prostate Carcinoma

Prostate carcinoma is the highest source of cancer-related fatalities in Western developed countries [110][83], with over 1,64,690 records and 29,430 deaths in 2018. Though rapid innovations in early identification and novel therapy techniques can significantly boost these patients’ lives, a significant proportion of them acquire aggressive and refractory tumors with a bad prognosis. Several bioactive compounds have been tried as adjuvants to existing therapy for treating and preventing hormone-refractory pancreatic cancer, but no clinical success has been found [123][93]. MTT and colony formation assays revealed that A. muricata fruit pulp extract has potent antiproliferative activity in prostate cancer (PCa) cell lines 22Rv1, LNCaP, and PC-3 at a concentration of 1–5 μg/mL [124][94]. They also discovered that fruit extract had antiproliferative effects, which were mediated by lowering HIF-1 expression and inhibiting NOX activity (Figure 3) [125][95]. Muricin J, muricin K, and muricin L induced antiproliferative and apoptotic effects on PC-3 cells at 20 µg/mL [126][96]. Muricin M, muricin N, and muricenin obtained from the A. muricata fruit bioactive ethanolic extract were shown to have antitumor effects at a concentration of 20 µg/mL [124][94].
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Figure 3. Schematic presentation of the anti-proliferative activity of graviola fruit extract against prostate cancer cell lines (a), the role of graviola against breast cancer cell line MCF-7 (b), and the molecular mechanism of A. muricata extract-treated HepG2 cell (c).
A. muricata leaf extract, the fraction with enriched flavonoids and acetogenins, possesses antiproliferative activity. The IC50 values were 63 µg/mL, 57 µg/mL, and 87 µg/mL against the prostate cancer cell line, PC-3. This study has proven the relevance of employing whole-leaf extracts to achieve maximum inhibitor potency in cancer treatment [127][97] .
Aqueous leaf extract possesses antiproliferative activity against BPH-1 (human benign prostatic hyperplasia) cells; cell viability decreased from 100% to 47% as the dose increased from 0 to 1.5 mg/mL, and aqueous extracts of the leaf were found to minimize prostate size, which may be because of apoptosis [131][98]. According to the available evidence, antiproliferative activity has been demonstrated by muricins J, K, L (20 µg/mL) [126][96] and muricins M, and N along with muricenin (20 µg/mL) [124][94]. Regarding antiproliferative activity of annomuricin E, its IC50 value on HT-29 cells was found to be 5.72 ± 0.41 μg/mL (12 h treatment), 3.49 ± 0.22 μg/mL (24 h treatment) and 1.62 ± 0.24 μg/mL (48 h treatment) [67][99]. Solvents including hexane (A. muricata fruit extract, 20 µg/mL), ethyl acetate extract [37], methanol leaves extract IC50 value against HEP-2 cell line (54.92 ± 1.44 μg/mL) [132][100], ethanol extract, and water extract [133][101] have antiproliferative impacts. Muricin J, muricin K or muricin L, muricin M, and muricin N, as well as muricenin, showed antiproliferative effects against PC-3 cancer cells [124,126][94][96].

5.4. Breast Cancer

The most prevalent malignancy among women worldwide is breast cancer [110][83]. Early-stage breast cancer may be treated, but advanced breast cancer has no treatment options. New chemopreventive and chemotherapeutic drugs are desperately needed in order to impede the formation of tumors and reduce associated morbidity. Although certain natural chemicals have been examined in vitro and shown to be safer and less hazardous than synthetic compounds [134][102], these natural compounds’ low clinical efficacy has hampered their translational use. Recent studies have demonstrated A. muricata’s strong antiproliferative and antitumor ability. Exposure of cancer cells to A. muricata leaf extract and ethyl acetate fraction resulted in morphological alterations indicative of apoptosis, a process characterized by the rupture and loss of the membrane and nucleus of cells. Reduced Bcl-2 and PARP-1 and increased caspase-9 and caspase-3 expression are responsible for the cytotoxic activity observed in MCF7 cells [62][103]. Treatment of Annonacin (0.5–1 µM) induced MCF breast cancer cell line death at 48 h and treatment of Annonacin (0.1 µM) in xenografts tumor decreases the expression of ER, cyclin D1, and Bcl2 (Figure 3) [135][104]. A. muricata fruit extract inhibited MDA-MB-468 cells (IC50 = 4.8 µg/mL) and significantly downregulated EGFR mRNA expression, cell cycle arrest, and apoptosis but not in MCF-10A cell lines. In the xenograft mouse model, 5-week dietary treatment with fruit extract (200 mg/kg diet) decreased expression of EGFR, p-EGFR, and p-ERK in MDA-MB-468 tumors by 56–32.5% [136][105]. MDR is the predominant source by which tumor cells gain therapeutic resistance, leading to therapy failure and tumor progression. By depleting ATP content, ACG bullatacin (1 µg/mL) is cytotoxic to the MCF-7/ADR cell line of multidrug resistant breast cancer [137][106]. ACGs from A. muricata offer a particular benefit against MDR breast tumors, whereas ACGs extracted from Annona Squamosa seeds alter mitogen-activated protein kinase (MAPK) signaling and triggered apoptosis in MCF-7/ADR cells. Annosquacin B (AB), dramatically reduced cell viability on MCF-7/ADR (IC50value-14.69 µM), induced apoptosis followed by elevated levels of caspase-3, caspase-9, Bax/Bcl-2, p-p38 MAPK and lowered p-JNK [138][107] .

5.5. Colon Carcinoma

CRC (colorectal carcinoma) is the third most common cause of cancer-related fatalities [110][83]. The biggest problems for CRC patients are therapeutic resistance and toxicity against current medications, which are connected to a poor prognosis [145][108]. A. muricata and other natural products have proven to be effective in preventing and treating CRC. The molecular mechanisms of various A. muricata extracts against CRC have recently been elucidated. In the COLO-205 (human colon adenocarcinoma) cell line, the A. muricata leaf extract (1422 ng/mL) also showed anticancer properties by increasing the proapoptotic protein caspase-3 [146][109] (Figure 4). The ethyl acetate leaf extract of A. muricata has a substantial cytotoxic effect on HCT-116 (human colorectal carcinoma) and HT-29 (human colorectal adenocarcinoma) cell lines (Figure 4), and IC50 values were 11.43 ± 1.87 µg/mL and 8.98 ± 1.24 µg/mL, respectively, followed by cell cycle arrest, apoptosis, mitochondrial membrane depolarization, cytochrome c leakage and activation of the initiator and executioner caspases, up-regulation of Bax and down-regulation of Bcl-2 proteins, halted the migration and invasion of HT-29 and HCT-116 cells [109][82].
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Figure 4. Schematic representation of molecular mechanisms of Annona muricata extracts against CRC (a), apoptosis induction in Annomuricin E treated HT-29 colorectal cancer cells (b), and apoptosis induction and mechanism of action in colorectal cancer-treated cell lines (c).
Phytochemical constituents of A. muricata, such as Annomuricin A (ED50 value of >1.0 µg/mL), Annomuricin B (ED50 value of 4.35 × 10−1 µg/mL), Annomuricin C (ED50 value of 1.54 µg/mL), Annomuricin E (ED50 value of 6.68 × 10−2 µg/mL), and muricapentocin (ED50 value of 7.10 × 10−2 µg/mL), were also found to be cytotoxic to HT-29 cells [147,148,149][110][111][112]. ACG desacetyl uvaricin (IC50 value of 14 nM) has also been shown to cause DNA damage by inactivating the MAPK pathway and producing superoxide, resulting in the growth inhibition of SW480 cells [150][113] (Figure 4). Annomuricin E derived from A. muricata leaves induced apoptosis in HT-29 cell line via caspase activation 3/7 and 9, Bax upregulation, and Bcl-2 down-regulation at the mRNA and protein levels.
Annomuricin E halted HT-29 cell proliferation, HCT-116 with an IC50 value of 1.62 ± 0.24 μg/mL, 32.51 ± 1.18 μg/mL after 48 h, followed by G1 cell cycle arrest and excessive accumulation of ROS-induced apoptosis in colorectal HT-29 and HCT-116 cancer cells, which was accompanied by MMP degradation, cytochrome c leakage, initiator and executor caspase activation, Bax upregulation, and Bcl-2 protein down-regulation (Figure 4). In rat colorectal carcinogenesis caused by azoxymethane, the ethyl acetate leaf extract reduced the inhibition of aberrant crypt foci by 72.5 % [67][99].

5.6. Head and Neck Cancers

The majority of head and neck malignancies arise from the mucosal epithelium of the oral cavity, pharynx, and larynx, and are generally referred to as head and neck squamous cell carcinoma (HNSCC) [151][114] and are the sixth highest prevalent cancer worldwide. Several anticancer drugs, such as etoposide, cisplatin, topotecan, doxorubicin, and fluorouracil (Figure 5), have been linked to adverse side effects that severely limit their utility. Through current advancements in the understanding and treatment of the disease, patients with HNSCC have a poor prognosis due to resistance to available chemoradiotherapy. As a result, there is a critical need to investigate less toxic anticancer compounds.
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Figure 5. Schematic representation of (a) comparison of chemoradiotherapy treatment and combination of Cisplatin and Annona muricata extract treatment for HNSCC and their side effects and (b) globally diagnosed types of hematological malignancies.
Aqueous A. muricata leaf extract possesses antiproliferative activity against the tongue squamous cell carcinoma patient-derived cell line SCC-25 (12.42 µg/mL) and induces G2/M cell cycle arrest [133][101]. With radiation therapy or in combination with other chemotherapeutic medicines, cisplatin’s efficacy against HNSCC increases dramatically, suggesting that cisplatin mixed with A. muricata could have significant anticancer effects on HNSCC [152][115]. Radiation is well-known to cause DNA damage, which initiates apoptosis, which is controlled by the proteins p53, Bcl2, and Bax. For radiation-induced apoptosis, a high amount of wild-type p53 is necessary. Therefore, the p53 status may be a critical factor in determining the radiosensitivity of tumor cells. The radiosensitivity of patients with head and neck cancer is determined by the ratio of p53, Bcl2, and Bax protein levels. Patients with cancer who had elevated Bcl2 levels were radioresistant. Overexpression of Bax and c-myc may increase head and neck cancer patients’ radiosensitivity [153][116]. Bax and c-myc overexpression may guarantee radiosensitivity in patients with head and neck cancer [153][116]. Therefore, the combination of A. muricata extracts with cisplatin would be more successful due to its involvement in inducing apoptosis. The ability of a leaf fraction from A. muricata to induce caspase 3 expression in cells cultivated from WHO stage III nasopharyngeal carcinoma biopsy tissue was studied. Compared to the control group, the treatment group had increased caspase 3 expression. The maximum expression was attained 24 h after treatment. Caspase 3 expression increased with increasing dosages of A. muricata leaf fraction, most notably at 125 µg/mL and 250 µg/mL [154][117]. Activating caspase 3/7 and caspase 9 expression is a key step in inducing apoptosis, which is caused by the A. muricata leaf fraction (Acetogenin) [67][99].

5.7. Hematological Malignancies

B-cell chronic lymphocytic leukemia, acute myeloid leukemia, multiple myeloma, and non-lymphoma Hodgkin’s make up about 4% of cancers diagnosed globally (Figure 5) [110][83]. Despite the disease’s biological characteristics and complexity, it poses particular clinical challenges. In clinical trials, phytocompounds and derivatives have been evaluated, but the majority of compounds have been unsuccessful due to inadequate effectiveness, resulting in resistance; therefore, it is imperative to develop novel natural chemical compounds with improved therapeutic capabilities. Though random screening is a high-priced and tedious process, focused research into commonly used medicinal plants can speed up the development of new anticancer drugs [155][118]. A. muricata twig, root, and leaf extract possess antiproliferative activity, and the IC50 values were found to be 49 ± 3.2 µg/mL, 9 ± 0.8 µg/mL, 14 ± 2.4 µg/mL, respectively, and apoptotic effects have been linked to cell cycle arrest and MMP loss in mechanical experiments [156][119]. Furthermore, ethanol and methanol A. muricata leaf extract-induced apoptosis in K562 (human myelogenous leukemia), CCRF-CEM (human T-leukemia), and CEM/ADR5000 (multidrug-resistant leukemia) cells have been reported [101][74]. In this study, it was found that A. muricata can be used to identify phenotypes of multidrug-resistant malignancy and is thus an outstanding method for the evolution of new therapeutic medicines for hematological malignancies. Methanolic extracts from seeds, leaves, and pericarp have shown antiproliferative activity, and the IC50 values were found to be fruit pericarp 4.58 ± 0.25 µg/mL, leaves 0.57 ± 0.02 µg/mL, and seeds 0.36 ± 0.03 µg/mL against CCRF–CEM cells and induced apoptosis, whereas pericarp and leaf extracts induce apoptosis in leukemia cells CEM/ADR5000 [37]. An ethanolic leaf extract at a 50 µg/mL concentration significantly increased caspase3 activity to induce apoptosis in K562 leukemia cancer cells, as reported by the TUNEL assay [157][120] .

5.8. Liver Cancer

The plant extracts have been shown to have a cytotoxic impact on hepatic cancer cells, hinting that they could be employed as a hepatic cancer treatment. The HepG2 cell line was shown to be inhibited in growth and viability after being incubated with an ethanol extract of A. muricata; after 24 and 48 h of treatment and LD50 values were 180 and 80 µg/mL, respectively, and apoptosis through inducing ROS pathway [159][121]. A. muricata leaf extracts possess antiproliferative activity, and the IC50 values were 150 μg/mL for both HepG2 and HCT116 cells, inducing apoptosis at a concentration of 120 μg/mL against HepG2 cells. HSP70, GRP94, and PDI-related protein 5 (Figure 3) were all found to be upregulated after HepG2 treatment [160][122] .

5.9. Cervical Cancer

In HeLa cervical cancer cells, different solvent leaf extracts were able to induce antiproliferative activity. As shown by the (3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazole) (MTT) reduction method, A. muricata methanol leaf extract was able to inhibit the proliferation of the HEp-2 (laryngeal cancer) cell line [132][100]. However, later HEp-2 was confirmed to be a HeLa cell line that had been cross-contaminated [162][123].

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