IMJM Volume 17 No.

3, December 2018

Anticancer Activity of Acetogenins from Annona

REVIEW ARTICLE

Muricata Fruit
Djabir Daddiouaissaa & Azura Amidb
a
Kulliyyah of Engineering, International Islamic University Malaysia (IIUM), Jalan Gombak, 53100 Kuala
Lumpur, MALAYSIA
b
International Institute for Halal Research and Training (INHART), Level 3, KICT Building, International
Islamic University Malaysia (IIUM), Jalan Gombak, 53100 Kuala Lumpur, MALAYSIA

ABSTRACT

Medicinal plants become very important in our days for their therapeutic benefits to humankind. It sustains
human health, and it is commonly known as herbal medicines since ancient times. Annona muricata is a
heart-shaped fruit that is consumed raw or as the fruit juice in the tropical area. A. muricata is used in
traditional and alternative medicine to treat different ailments such as diabetes, hypertension, respiratory
and skin illness, inflammation and cancer. A. muricata contains essential anticancer agents named
acetogenins that play the significant role in various cancer types. Acetogenins are strong nicotinamide
adenine dinucleotide oxidase inhibitors of the cancer cell's mitochondrial membrane but showed neurotoxic
effects in rats. Therefore, acetogenins need to be further investigated to determine the exact mechanisms
of action, long-term safety, optimal dosage, and potential side effects. Given the extensive studies on A.
muricata, this review focuses on the phytochemistry, medicinal uses, biological activities and the
mechanisms of action for the fruit extracts and acetogenins, to stimulate further studies on the fruit pulp
used for human consumption.

KEYWORDS: Acetogenins, Anticancer, Annona muricata, complex I mitochondrial.

INTRODUCTION

Natural products from plants have been used for a traditional uses is Annona muricata L.2 A. muricata is
considerable period by many cultures and a species in the Annonaceae family that obtained
civilizations to help humankind maintain its health much interested in the last decades due to its
and treat different diseases. Over the centuries, the pharmaceutical potential. A long time ago, many
phytochemical compounds have been an essential studies reported on the medicinal use of the
discovery in pharmaceutical applications. The Annonaceae family, since then, the bioactivity and
significance of the active compounds from plants in toxicity of this species attracted the attention of
medicine and agriculture has stimulated scientific many researchers.2,3 Among the critical subject
interest in its biological properties.1 In a studied related to A. muricata is its acetogenins.
pharmaceutical area, plants used in ethnomedicine This study will extensively collect relevant
are the most abundant source of active information regarding A. muricata acetogenins to
phytochemicals that afford health benefits against identify the uncover information so that further
different ailments and diseases. One of it with many investigation will be made.

BOTANICAL DESCRIPTION AND DISTRIBUTION

Corresponding Author:
Prof. Dr. Azura Amid A. muricata is commonly known as soursop (English),
Institute for Halal Research and Training (INHART), graviola (Portuguese), guanabana (Latin; South
Level 3, KICT Building, America) and many other indigenous names. This
International Islamic University Malaysia,
plant species belongs to the genus of Annona and the
Kuala Lumpur, Malaysia
Email: [email protected] Annonaceae family; the order of Magnoliales and
Magnoliophyta Division.4 The Annona genus contains

103
IMJM Volume 17 No. 3, December 2018
more than 70 species in which A. muricata is widely with a diameter which varies between 5-20 cm and
grown.3 A. muricata distributes in the warmest an average weight of 0.4 to 1.0 kg (Figure 1). Each
tropical region of Central and South America, fruit may include 55–170 black seeds.4 The pulp of
Southeast Asia and Western Africa.4 It grows at the fruit has a sweet flesh, and typical flavor which
altitudes below 1200 m above sea level, and can be eaten and used as an ingredient in the
temperatures between 25 and 28 °C, with humidity preparation of many foods and is perfect for making
between 60 and 80% and annual precipitation over drinks, candy and ice cream. Also, the edible fruit,
1500 mm. leaves, seeds, and root are known to have attractive
medicinal properties.5

ETHNO MEDICINAL USE

All portions of A. muricata tree such as leaves,

twigs, fruit, and seeds are used against many human
ailments and diseases, particularly cancer and
parasitic infection.6 The fruit is taken as herbal
medicine to eliminate worms and parasites, for
arthritic pain, diarrhea, neuralgia, dysentery,
Figure 1. Annona muricata L fruit rheumatism, cold fever and to increase mother's
milk after childbirth.7 Table I lists the
A. muricata is a 4 to 6 meters high evergreen tree ethnomedicinal use of A. muricata fruit.
with large, glossy, dark green leaves.1 Its edible
fruits are large, heart-shaped, dark green in color,

Table I: Ethnomedicinal use of A. muricata fruit in the world

Worldwide Ethnomedicinal use Preparation/ References

ethnomedicinal use application

Bolivia Kidney disorders, hypertension Juice/oral 10

Brazil Lactagogue, astringent, diarrhea, dysentery Juice/oral 8

Colombia Febrifuge, inflammation Juice/oral 11

The Dominican Republic Galactogogue Infusion/oral 12

Haiti Fevers, flu, heart affectation parasite,

pellagra, anxiety, febrifuge, diarrhea, and NR 8
lactagogue

Jamaica Fevers, parasites, diarrhea, and lactagogue Juice/oral 13

Malaysia Stomach pain, hypertension Juice/oral 14

Mexico Dysentery, diabetes Juice/oral 15

The Philippines Diabetes Pulp/oral 8

Peru Obesity, gastritis, dyspepsia, diabetes, Pulp, juice/ oral 8

inflammation, and cancer

Uganda Diabetes Pulp/oral 16

West Indies Fevers, parasites, diarrhea, and Poultice/oral 13

galactagogue

104
 IMJM Volume 17 No. 3, December 2018
Recently, A. muricata fruit consumption Many phytoconstituents and compounds found in
11
increased. Researchers identified bioactive different parts of A. muricata, including alkaloids
compounds such as acetogenins and polyphenols in (ALKs), phenolics (PLs), megastigmanes (MGs),
its pulp, which are related to different pathology flavonol triglycosides (FTGs), cyclopeptides (CPs)
prevention including neurodegeneration, diabetes, and essential oils.1 Additionally, A. muricata has
cardiovascular and anti-inflammatory diseases.8 At shown to be the most abundant source of the
present, the attention is being focused on annonaceous acetogenin compounds (AGEs), in
anticancer properties of A. muricata acetogenins which, researchers have identified more than 120
which are the primary bioactive compounds found acetogenins from methanolic, ethanolic or another
in the fruit.9 organic extract of different part of A. muricata such
as leaves, seeds, bark, stems, pulp and fruit
PHYTOCHEMICALS peel.20,21

A. muricata flesh fruit consists of 80% water, 18% ANNONACEOUS ACETOGENINS

carbohydrates, 1% protein and small quantities of
vitamins B, B2, C and dietary fiber.17 A. muricata Acetogenins are secondary metabolites of C35/C37
fruit contains various significant minerals too, such deriving from the long chain of unsaturated fats in
as potassium (K), calcium (Ca), sodium (Na), copper the polyketide pathway. A methyl-substituted α, β-
(Cu), iron (Fe) and magnesium (Mg). Because of its unsaturated γ-lactone form them, which is usually
nutritional values, Gymfi and co-workers (2011) combined with fatty acids with a two-propanol unit
suggested that the A. muricata fruit can provide at C-2 (Figure 2).20,22
essential elements and nutrients to the human
body.18

OH OH
2 4 O O 32/34
n m
OH
O
35/37 O 1

Figure 2: General structure of acetogenins.

AGEs are the main bioactive compounds of the ubiquinone oxidoreductase).25 Biological studies
Annonaceae family.23 Since 1982 when Jolad et al. and phytochemical investigations of the A. muricata
discovered uvaricin from Uvaria accuminata, more fruit brought a wide range of AGE compounds, as
than 500 AGEs have been identified from various summarized in Table II.
parts of plants in the Annonaceae family. 24 In recent
years, many scientific studies focused on AGEs The chemical structures of the essential AGEs
because of their unusual structures and extensive extracted from A. muricata fruit were shown in
biological activities. Some studies have shown that Figure 3. To the best of our knowledge, at the time
AGEs are more cytotoxic than alkaloids and of preparation of this paper (May 2018), at least 20
rotenone.3 AGEs have been identified and isolated from the A.
muricata fruit pulp.
The biological activities of AGEs, which are known
as anticancer are initially by inhibiting the complex
I mitochondrial of the cell (mitochondrial NADH:

105
IMJM Volume 17 No. 3, December 2018

Table II: Annonaceous acetogenins extracted from A. muricata fruit (AGE) and its biological activities.
Stage of Mechanism of
Compounds Biological Activity References
study action
Annonamuricin A,
Inhibition of human prostate cancer
B, C, D In vitro NR 9
PC-3 cells
Inhibition of PC-3 cells
Annonacin In vitro NR 9
Inhibition of PC-3 cells
Muricin M In vitro NR 26
Inhibition of PC-3 cells
Muricin N In vitro NR 26
Inhibition of PC-3 cells
Muricenin In vitro NR 26
Inhibition of the
Muricin J In vitro Inhibition of PC-3 cells complex I 27
mitochondrial.
Inhibition of the
Muricin K In vitro Inhibition of PC-3 cells complex I 27
mitochondrial.
Inhibition of the
Muricin L In vitro Inhibition of PC-3 cells complex I 27
mitochondrial.
Cytotoxicity against human
Annoreticuin-9- pancreatic tumor (PACA-2), lung
In vitro 20
one carcinoma (A-549) and prostate NR
adenocarcinoma (PC-3) cell lines
Cytotoxicity against human
Cis-annoreticuin In vitro hepatoma cell line (Hep G2) 20
NR
NR
Sabadelin -- NR 20
NR
Epomuricenins-A -- NR 28
NR
Epomuricenins-B -- NR 28
NR
Epomusenin-A -- NR 28
NR
Epomusenin-B -- NR 28
NR
Epomurinin-A -- NR 28

Epomurinin-B -- NR NR 28

Anticancer Activity and Mechanism of Action of Previous data reported that A. muricata has an
Acetogenins ability on growth inhibition against a wide variety of
cancer cells, including solid breast tumor, lung
Cancer is among the most common causes of carcinoma cell lines, prostate adenocarcinoma,
morbidity and mortality in the world, about 1.73 colon adenocarcinoma cell lines. As well as on
million new cancer cases and 609,640 cancer deaths pancreatic carcinoma cell lines, human lymphoma
are projected to occur in the United States in cell lines, liver cancer cell lines and multi-drug
2018.29 Many studies reported on the significance resistant human breast adenocarcinoma.32,33
cytotoxicity of different extracts and isolated AGEs
from a different part of A. muricata towards various Among many active ingredients, acetogenins
cancer cell lines.30,31 However, few of these studies modulate the production of mitochondrial adenosine
have illustrated or focus on the benefits of the fruit triphosphate (ATP) of cancer cells. ATP reduces the
pulp against cancer disease. Mainly, the acetogenins nourishment of cancer cells by decreasing the
extracted from the fruit pulp of A. muricata and its growth of blood vessels. Previous studies have
mechanism of actions. proposed that the mechanism of the cytotoxic
action of acetogenins is the inhibition of the

106
 IMJM Volume 17 No. 3, December 2018

mitochondrial complex I by the inhibition of complex I diminish NADH oxidation which lowers the
ubiquinone-linked NADH oxidase in the membrane proton gradient through the internal mitochondrial
causing apoptosis in cancer cells.34,35 membrane and the ATP synthesis. Moghadamtousi et
al. have confirmed it by demonstrating that the
Complex I, the most complicated proton pump of extracts of A. muricata can arrest cancer cells
the respiratory chain encoded by the nuclear and development in G0/G1 phase which caused by the
mitochondrial genomes, which is responsible for disruption of the mitochondrial membrane, and the
NADH oxidation, the hydrogenase of released induction of apoptosis to suppress the invasion and
electrons to electron acceptor ubiquinone and the migration of cancer cells.37
proton translocation module.36 Inhibition of

trans
threo OH threo

( )8 ( )5
O
OH O
HO HO
O
Annonamuricins A

trans
threo threo

() () ( )5
n m O
HO HO OH OH O
O
Annonamuricins B) m=2 n=7
C) m=1 n=8

trans
threo threo HO

() ()
9 O 6
HO OH O
HO
O
Annonamuricins D

() () ()
9 O 2 3
HO OH OH O
HO
O
Annonacin

trans
HO threo

() ()
O 7
6
OH O
threo OH OH
O
Muricin M

107
IMJM Volume 17 No. 3, December 2018

trans
threo threo

() ()
8 O 7
OH OH OH O
OH
O
Muricin N

trans
threo threo OH

() ()
9 O 4
OH OH O
OH
O
Muricenin

trans
erythro threo

() ()
9 O 6
OH OH OH O
OH
O
Muricin J

trans
threo threo

() ( )5 O ()
4 5
OH OH O
OH OH
O
Muricin K

trans
threo HO threo

() ()
5 O 8
OH O
OH OH
O
Muricin L

HO HO O O
32 O
() () () O
11 5 3
OH
35
Annoreticuin-9-one

HO HO HO O

O
() () () O
11 5 3
OH

Cis-annoreticuin

OH

O
()
()
11 7
O O
Sabadelin

O 1 O
2
32 35
19 O 15 33

Epomuricenins-A

108
 IMJM Volume 17 No. 3, December 2018

O
O

32 35
17 O 13

Epoxymurin-A

O 1
O
2
34 37
21 O 17 35

Epomusenins A

O
O

34 37
15
19 O

Epomusenins B

O 1
O

2
32 15 35
O 33
Epomurinins-A

O
O

32 13 35
O

Epomurinins-B

Figure 3: Chemical structures of the major acetogenins isolated from A. muricata fruit.

Moreover, the complex I dysfunction provoke muricata were suggested including the inhibition of
the activation of the mitochondrial-dependent multiple signaling pathways, metastasis, cell cycle
apoptotic machinery via triggering liberation of arrest and induction of necrosis.33,40 Ko and co-
apoptogenic molecule cytochrome c from defective workers also reported that bullatacin extracted from
mitochondria.36 Another study reported that A. muricata at doses of 0.4 g/kg could reduce a
Annomuricin E caused depletion of mitochondrial tumor induced in rodents 300 times better than the
membrane potential (MMP) which leads to the drug Taxol (paclitaxel).41 Meanwhile, Wang and co-
formation of apoptosome and the activation of workers reported that annonacin decreased tumour
caspase 9 and caspase 3/7, which have a relation size in murine models at doses of 0.01 mg/kg
with mitochondrial death pathway.38 Additionally, compared to the commercial drugs such as
Annonacin E upregulated Bax protein and down- adriamycin and cisplatin.42
regulates Bcl-2 proteins. This result confirms
that Annonacin E caused apoptosis through the Although there are many AGEs isolated and
mitochondrial-mediated pathway. The AGEs identified from A. muricata fruit, there is
apoptosis effect is selective for cancer cells is insufficient understanding of its mechanisms of
related to high ATP demand in cancer cells as action in reducing tumor or cancer cells.20,21
suggested by McLaughling that selective cytotoxicity Therefore, more study is needed to understand how
of A. muricata extracts is because of the enhanced AGEs work entirely. These significance anticancer
ATP request of tumor cells compared to the healthy and antitumor activities selected for A. muricata is
cells.39 due to the active compounds, especially AGEs that
can be utilized as a cancer adjuvant treatment. 30
In vivo studies reported the anticancer activity of
isolated acetogenins from A. muricata fruit reduced Study on Neurotoxin Effect of Acetogenins
a breast tumor in rats when treated with A. The dysfunction of mitochondrial CI relates to a wide
muricata fruit extract for 5 weeks.40 Many range of neurodegenerative diseases.36 A published
mechanisms of action of the cytotoxicity of A. study in the Lancet Journal in 1999 investigated the

109
IMJM Volume 17 No. 3, December 2018
relationship between the consumption of A. More research is needed to identify AGEs mechanism
muricata fruit and the occurrence of atypical of actions and quantify the neurotoxic molecules
parkinsonian syndromes observed in the French effects and determine the toxicity level to human.
West Indies on 87 patients.43 Furthermore, the Finally, more clinical studies are required to verify
etiology of that disease in Guadeloupe and validate the plant extracts safety, to be
Island showed a close correlation between adopted as a therapeutic anticancer agent.
acetogenins consumption and appearance of the
neurodegenerative illness.44 A recently published REFERENCES
study reported that annonacin as a significant AGE
in A. muricata might be a potential risk factor for 1. Moghadamtousi SZ, Fadaeinasab M, Nikzad S,
neurodegenerative diseases.45 In rodent striatal et al. Annona muricata (Annonaceae): A
neurons, annonacin minimized the ATP supply and review of its traditional uses, isolated
interrupted the mitochondrial transportation to the acetogenins, and biological activities.
cell soma; this caused perturbations in the protein International Journal of Molecular Sciences
tau which led to similar characteristics of 2015a;16(7):15625–15658.
neurodegenerative diseases.44 It is anticipated that 2. Billo´ nH. Histoire des plantes. Librairie de L.
if somebody consumes one fruit of A. muricata Hachette, Paris 1869 ; pp. 275–276.
daily, following one year, the aggregate amount of 3. Coria-Téllez AV, Montalvo-Gónzalez E, Yahia
annonacin that has ingested is adequate to induce EM, et al. Annona muricata: A comprehensive
brain lesions in rats.46 review of its traditional medicinal uses,
phytochemicals, pharmacological activities,
However, the number of the human population mechanisms of action and toxicity. Arabian
studied and the study in the rat may not represent a Journal of Chemistry 2015.
broader community of human in another area or 4. Pinto AC, de Q, Cordeiro MCR, et al. Annona
continents. Because A. muricata is not new to those muricata. In: Williams, J.T. (Ed.), Annona
in warm tropical regions and a study by Muangpaisan species, taxonomy and botany international
and co-workers showed that the prevalence of centre underutilised crops. University of
Parkinson's diseases in Asian countries was slightly Southampton, Southampton, UK 2005; pp. 3–
lower than that in Western nations, although A. 16.
muricata consumption is a routine practice among 5. Ioannis P, Anastasis S, and Andreas Y.
this people.47 Despite some in vitro and in vivo Graviola : A systematic review of Its aticancer
studies reported on its neurotoxic compounds, properties 2015;3(6):128–131.
Awodele and co-workers demonstrated that 6. Gajalakshmi S, Vijayalakshmi S, Rajeshwari
consumption of A. muricata fruit for 60 consecutive Devi V. Phytochemical and pharmacological
days did not induce any significant toxicity in a rat properties of Annona muricata: A review, Int J
model.48 Therefore, an in-depth study on the Pharm Sci 2012;4(2):3-6.
mechanism of action in vitro and in vivo and 7. Yajid AI, Ab Rahman HS, Wong MPK, et al.
optimize consumption dosage at a specific AGEs Potential benefits of Annona muricata in
must be carried out. combating cancer: A review. The Malaysian
journal of medical sciences: MJMS 2018;25
CONCLUSION (1):5.
8. Badrie N, and Schauss AG. Soursop (Annona
A. muricata fruit, an indigenous medicinal plant muricata L.): composition, nutritional value,
used for ages to treat many diseases. Many types of medicinal uses, and toxicology. Bioactive
research have proven that A. muricata possesses a Foods in Promoting Health 2010;621-643.
wide range of biological activities, and the most 9. Sun S, Liu J, Sun X, et al. Novel Annonaceous
likely are anticancer, antidepressive and acetogenins from Graviola (Annona muricata)
antiparasitic activity. However, there are limited fruits with strong anti-proliferative activity.
studies on A. muricata phytoconstituents and Tetrahedron Letters 2017;58(19):1895–1899.
compounds, especially acetogenins reported on its 10. Hajdu Z, and Hohmann J. An
cytotoxic to the cancer cells especially on its ethnopharmacological survey of the traditional
mechanism of actions. Nevertheless, it is also said medicine utilized in the community of
to have a neurotoxic effect. Porvenir, Bajo Paraguá Indian Reservation,

110
 IMJM Volume 17 No. 3, December 2018

Bolivia. Journal of Ethnopharmacology Acetogenins from Annonaceae: recent progress

2012;139(3):838-857. in isolation, synthesis and mechanisms of
11. Betancur-Galvis LA, Saez J, Granados H, et al. action. Natural Product Reports 2005;22(2):269
Antitumor and antiviral activity of Colombian -303
medicinal plant extracts. Memórias do 23. Gavamukulya Y, Wamunyokoli F, and El-Shemy
Instituto Oswaldo Cruz 1999;94(4):531-535. HA. Annona muricata: Is the natural therapy to
12. Ross IA. Medicinal plants of the world, second most disease conditions including cancer
ed. Chemical Constituents, Traditional and growing in our backyard? A systematic review
Modern Medicinal 2010; 1:133–142. of its research history and future prospects.
13. Taylor L. Graviola. Technical data report for Asian Pacific journal of tropical medicine
Graviola, Annona muricata, 2002. 2017.
14. Samuel AJSJ, Kalusalingam A, Chellappan DK, 24. Jolad SD, Hoffmann JJ, Schram KH, et al.
et al. Ethnomedical survey of plants used by Uvaricin, a new antitumor agent from Uvaria
the Orang Asli in Kampung Bawong, Perak, accuminata (Annonaceae). Journal of Organic
West Malaysia. Journal of Ethnobiology and Chemistry 1982;47(16):3151-3153.
ethnomedicine 2010;6(1):5. 25. Zafra-Polo MC, González MC, Estornell E, et al.
15. Alonso-Castro AJ, Villarreal ML, Salazar-Olivo Acetogenins from Annonaceae, inhibitors of
LA, et al. Mexican medicinal plants used for mitochondrial complex I. Phytochemistry
cancer treatment: pharmacological, 1996;42(2):253-271.
phytochemical and ethnobotanical studies. 26. Sun S, Liu J, Zhou N, et al. Isolation of three
Journal of Ethnopharmacology 2011;133 new annonaceous acetogenins from Graviola
(3):945-972. fruit (Annona muricata) and their anti-
16. Ssenyange CW, Namulindwa A, Oyik B, et al. proliferation on human prostate cancer cell PC-
Plants used to manage type II diabetes 3. Bioorganic and Medicinal Chemistry Letters
mellitus in selected districts of central 2016;26(17):4382–4385.
Uganda. African health sciences 2015;15 27. Sun S, Liu J, Kadouh H, et al. Three new anti-
(2):496-502. proliferative Annonaceous acetogenins with a
17. Pier O. Pacific island ecosystem at risk, mono-tetrahydrofuran ring from graviola fruit
"Result set for Annonaceace Annona (Annona muricata). Bioorganic & medicinal
muricata." United States Geological Survey chemistry letters 2014;24(12):2773-2776.
and the United States Forest Service: Pier 28. Melot A, Fall D, Gleye C, et al. Apolar
species lists, 8, 2008. Annonaceous acetogenins from the fruit pulp of
18. Gyamfi K, Sarfo D, Nyarko B, et al. Assessment Annona muricata. Molecules 2009;14(11):4387–
of elemental content in the fruit of the 4395.
graviola plant, Annona muricata, from some 29. Siegel RL, Miller KD, & Jemal A. Cancer
selected communities in Ghana by statistics, 2018. CA: A cancer journal for
instrumental neutron activation analysis. Elixir clinicians 2018; 68:7–30.
Food Sci 2011;41:5671-5675. 30. Dai Y, Hogan S, Schmelz EM, et al. Selective
19. Leboeuf M, Cavé A, Bhaumik PK, et al. The growth inhibition of human breast cancer cells
phytochemistry of the by graviola fruit extract in vitro and in vivo
Annonaceae. Phytochemistry 1980;21 involving downregulation of EGFR
(12):2783-2813. expression. Nutrition and cancer 2011;63
20. Ragasa CY, Soriano G, Torres OB, et al. (5):795-801.
Acetogenins from Annona 31. Paul J, Gnanam R, M Jayadeepa R, et al. Anti-
muricata. Pharmacognosy Journal 2012;4 cancer activity on Graviola, an exciting
(32):32-37. medicinal plant extract vs. various cancer cell
21. Champy P, Gue´ rineau V, and Lapre´ vote O. lines and a detailed computational study on its
MALDI-TOF MS Profiling of Annonaceous potent anti-cancerous leads. Current topics in
Acetogenins in Annona muricata products for medicinal chemistry 2013;13(14):1666-1673.
human consumption. Molecules 14 2009; 5235– 32. Liaw CC, Chang FR, Lin CY, et al. New
5246. cytotoxic monotetrahydrofuran Annonaceous
22. Bermejo A, Figadère B, Zafra-Polo MC, et al. Acetogenins from Annona muricata. Journal of

111
IMJM Volume 17 No. 3, December 2018

natural products 2002;65(4):470-475. 44. Escobar-Khondiker M, Höllerhage M, Muriel MP,

33. Torres MP, Rachagani S, Purohit V, et al. et al. Annonacin, a natural mitochondrial
Graviola: a novel promising natural-derived complex I inhibitor, causes tau pathology in
drug that inhibits tumorigenicity and cultured neurons. Journal of Neuroscience
metastasis of pancreatic cancer cells in vitro 2007;27(29):7827-7837.
and in vivo through altering cell 45. Bonneau N, Le Ven J, Schmitz-Afonso I, et al.
metabolism. Cancer letters 2012;323(1):29-40. Annonaceous acetogenins as environmental
34. Lannuzel A, Michel PP, Hoˆ glinger GU, et al. neurotoxins: Human exposure from edible
The mitochondrial complex I inhibitor annona fruits. Planta Medica 2012;78(11):
annonacin is toxic to mesencephalic PH25.
dopaminergic neurons by impairment of 46. Champy P, Melot A, Guérineau Eng V, et al.
energy metabolism. Neuroscience 2003;121 Quantification of acetogenins in Annona
(2):287– 296. muricata linked to atypical parkinsonism in
35. Yang H, Liu N, Lee S. Ethanol extract of Guadeloupe. Movement Disorders 2005;20
Annona muricata L induces liver cancer cell (12):1629-1633.
apoptosis through ROS pathway. Biomedical 47. Muangpaisan W, Hori H, and Brayne C. A
and Pharmacology Journal 2016;9(3):919–925. systematic review of the prevalence and
36. Chomova M, and Racay P. Mitochondrial incidence of Parkinson's disease in Asia.
complex I in the network of known and Journal of Epidemiology 2009;19(6):281-293.
unknown facts. Gen Physiol Biophys 2010;29 48. Awodele O, Ishola IO, Ikumawoyi VO, et al.
(1):3-11. Toxicological evaluation of the lyophilized
37. Moghadamtousi SZ, Karimian H, Rouhollahi E, fruit juice extract of Annona muricata Linn
et al. Annona muricata leaves induce G 1 cell (Annonaceae) in rodents. Journal of basic and
cycle arrest and apoptosis through clinical physiology and pharmacology 2014;25
mitochondria-mediated pathway in human (4):411-421.
HCT-116 and HT-29 colon cancer cells. Journal
of ethnopharmacology 2014; 156:277-289.
38. Green DR, and Kroemer G. The
pathophysiology of mitochondrial cell death.
Science 2004;305(5684):626-629.
39. McLaughlin JL. Paw Paw and cancer:
Annonaceous Acetogenins from discovery to
commercial products⊥. Journal of Natural
Products 2008;71(7):1311-1321.
40. Elisya Y, Kardono LB, and Simanjuntak P.
Tablet formulation of the ethyl acetate
soluble extract of soursop (Annona muricata
L.) leaves. Asian J. Appl. Sci 2014; 2:323-329.
41. Ko YM, Wu TY, Wu YC, et al. Annonacin
induces cell cycle-dependent growth arrest
and apoptosis in estrogen receptor-α-related
pathways in MCF-7 cells. Journal of
Ethnopharmacology 2011;137(3):1283-1290.
42. Wang LQ, Min BS, Li Y, et al. Annonaceous
acetogenins from the leaves of Annona
montana. Bioorganic & medicinal chemistry
2002;10(3):561-565.
43. Caparros-Lefebvre D, and Elbaz A. Possible
relation of atypical parkinsonism in the French
West Indies with consumption of tropical
plants: a case-control study. The Lancet
1999;354(9175):281-286.

112