Oxidative Medicine and Cellular Longevity / 2018 / Article / Tab 3

Review Article

Anticancer Properties of Graviola (Annona muricata): A Comprehensive Mechanistic Review

Table 3

Anticancer effects of AGEs and extracts derived from the different aerial organs of A. muricata.

CancersCell linesChemical compound or solventClassPlant partDose, IC50, ED50, GI50, LC50, IC25, and/or MICAnticancer effects

Breast cancerMCF-7Annomuricin AAGELeafCytotoxic activity [17]
Annomuricin B
Annomuricin CAGELeaf—–—Cytotoxic activity [86]
Annomuricin EAGELeafCytotoxic activity [16]
Muricatocin CAGELeaf—–—Cytotoxic activity [86]
MuricapentocinAGELeafCytotoxic activity [16]
AnnomutacinAGELeafCytotoxic activity [43]
(2,4-cis)-10R-Annonacin-A-one + (2,4-trans)-10R-annonacin-A-oneAGELeaf
AnnohexocinAGELeafSignificant cytotoxic activity [34]
Muricatocin AAGELeafCytotoxic activity [44]
Muricatocin BAGELeaf
Annopentocin AAGELeafCytotoxic activity [32]
Annopentocin BAGELeaf
Annopentocin CAGELeaf
cis-Annomuricin-D-one + trans-annomuricin-D-oneAGEsLeaf
Murihexocin AAGELeafSignificant cytotoxic activity [15]
Murihexocin BAGELeaf
Murihexocin CAGESeedCytotoxic activity [47]
MuricoreacinAGESeed
MuricatacinAGESeedCytotoxic activity [48]
IsoannonacinAGESeedCytotoxic activity [49]
Isoannonacin-10-oneAGESeed
GoniothalamicinAGESeed
GigantetrocinAGESeed and/or leaf
Gigantetrocin AAGESeedCytotoxic activity [50]
Muricatetrocin AAGESeed and/or leafCytotoxic activity [17, 50]
Muricatetrocin BAGESeed
Gigantetrocin BAGESeed
cis-AnnonacinAGESeedCytotoxic activity [85]
cis-Annonacin-10-oneAGESeed
cis-GoniothalamicinAGESeed
ArianacinAGELeaf
JavoricinAGELeaf
HexaneExtractLeafDoses: 1.56, 3.12, 6.25, 12.5, 25, 50, and 100 μg/mL; Significantly reduced cell proliferation in cancer cells [31]
Ethyl acetateExtractFruitDoses: 1.56, 3.12, 6.25, 12.5, 25, 50, and 100 μg/mL;
MethanolExtractLeafDoses: 1.56, 3.12, 6.25, 12.5, 25, 50, and 100 μg/mL;
———ExtractLeaf0, 50, 100, 150, and 200 μg/mL; Inhibited growth of cancer cells [23]
Ethanol (95%)ExtractLeafCytotoxic activity [45]
(+)-(3S,6S,7R,8S)-Periconone AFungal strain ExtractLeaf0.01–10 μmol/mLCytotoxic activity [38]
(−)-(1R,4R,6S,7S)-2-Caren-4,8-olide
MDA-MB-231HexaneExtractLeafDoses: 1.56, 3.12, 6.25, 12.5, 25, 50, and 100 μg/mL; Significantly reduced cell proliferation in cancer cells [31]
Ethyl acetateExtractFruitDoses: 1.56, 3.12, 6.25, 12.5, 25, 50, and 100 μg/mL; Significantly reduced cell proliferation in cancer cells [31]
MethanolExtractLeafDoses: 1.56, 3.12, 6.25, 12.5, 25, 50, and 100 μg/mL;
———ExtractSeedDoses: 50, 100, 150, and 200 μg/mL; Inhibited the growth of cancer cells [23]
MDA-MB-231-pcDNA3MethanolExtractPericarpCytotoxic activity [24]
MethanolExtractLeaf
MethanolExtractseed
MDA-MB-231-BCRP clone 23MethanolExtractPericarp
MethanolExtractSeed
MethanolExtractLeaf
———Ethanolic component (7,12-dimethylbenzeneanthracene (DMBA))ExtractFruitThree groups of albino mice treated intragastrically by gavage for 6 weeks: 20 mg/mL/week of DMBA + 200 mg/mL/day of extract, 20 mg/mL/week of DMBA + 100 mg/mL/day of extract and 20 mg/mL/week of DMBA + 50 mg/mL/day of extract [139]Prevented DMBA-induced DNA damage [77, 139]
Leaves boiled in waterBeverageLeafA 66-year-old female who has been diagnosed with cancer used to boil 10–12 dry leaves in water for 5–7 minutes, 8 oz PO daily at that timeHer metastatic breast cancer is still stable after 5 years on graviola and Xeloda after previously progressing on multiple lines of therapy [118]
MDA-MB-468———ExtractLeafDoses: 5, 25, 50, or 100 μg/mL; in vitro. In addition 200 mg/kg/35 week injected into the back of athymic mice in vivoInhibited EGFR-overexpression and EGFR mRNA expression. Induced cell cycle arrest at the G0/G1 phase. Induced apoptosis through caspase-3 activation. In vivo, it inhibited the growth of MDA-MB-468 tumors implanted in athymic mice (32% growth inhibition). It also significantly reduced the protein expression of EGFR, p-ERK, and p-EGFR in tumors [23]
MDAEthanolExtractLeafCytotoxic activity [93]
SKBR3EthanolExtractLeaf
T47DEthanolExtractFruitInduced cytotoxicity and apoptosis [22]
Bladder cancerECV-304EthanolExtractTwing0.1–10 mg/mL in vitro, and 0.5 g/kg into albino mice in vivo [96]Cytotoxic activity against cancer cells in vitro and within reduction of time reaction in vivo [96]
Prostate cancerPC-3Muricin J, K, or LAGEsLeafDose: 20 μg/mL (24 h)Antiproliferative activity against human cancer cells [29]
Annomuricin EAGELeafCytotoxic activity [16]
MuricapentocinAGELeaf
AnnohexocinAGELeafSignificant cytotoxic activity [34]
Annopentocin AAGELeafCytotoxic activity [32]
Annopentocin BAGELeaf
Annopentocin CAGELeaf
cis-Annomuricin-D-one + trans-annomuricin-D-oneAGEsLeaf
Murihexocin AAGELeafSignificant cytotoxic activity [15]
Murihexocin BAGELeaf
Murihexocin CAGEFruitCytotoxic activity [47]
Muricoreacin
Muricin MAGEfruitDose: 20 μg/mLAntiproliferative activities against human prostate cancer cells [30]
Muricin NAGEsLeaf
Muricenin
———WaterExtractLeafF344 male rats (≈200 g) were gavaged 30 mg/mL (10 rats) and 300 mg/mL (10 rats) and fed ad libitum alongside 10 control rats for two monthsReduced prostate size in vivo, possibly through apoptosis [21]
Colorectal cancerHT-29Annomuricin AAGELeafCytotoxic activity [17]
Annomuricin BAGELeaf
Annomuricin CAGELeaf—–—Cytotoxic activity [86]
Muricatocin C
Annomuricin EAGELeafDoses: 1, 2, 4, 8, and 16 μg/mL [25]; [16]; IC50: 5.72 ± 0.41 μg/mL (12 hr), 3.49 ± 0.22 μg/mL (24 hr), and 1.62 ± 0.24 μg/mL (48 hr) [25].Induced toxicity against cancer cells [16, 25]. Suppressed proliferation of cancer cells and induced lactate dehydrogenase leakage, cell cycle arrest at G1 phase, and apoptosis mediated through activation of caspases 3/7 and 9. Also induced a time-dependent upregulation of Bax and downregulation of Bcl-2 at both the mRNA and protein level [25]
MuricapentocinAGELeafCytotoxic activity [16]
AnnomutacinAGELeafCytotoxic activity [43]
(2,4-cis)-10R-Annonacin-A-one + (2,4-trans)-10R-annonacin-A-oneAGELeaf
AnnohexocinAGELeafSignificant cytotoxic activity [34]
Muricatocin AAGELeafCytotoxic activity [44]
Muricatocin BAGELeaf
Annopentocin AAGELeafCytotoxic activity [32]
Annopentocin BAGELeaf
Annopentocin CAGELeaf
cis-Annomuricin-D-one + trans-annomuricin-D-oneAGEsLeaf
Murihexocin AAGELeafSignificant cytotoxic activity [15]
Murihexocin BAGELeaf
Murihexocin CAGESeedCytotoxic activity [47]
MuricoreacinAGESeed
MuricatacinAGESeedCytotoxic activity [48]
IsoannonacinAGESeedCytotoxic activity [49]
Isoannonacin-10-oneAGESeed
GoniothalamicinAGESeed
GigantetrocinAGESeed and/or leaf
Gigantetrocin AAGESeedCytotoxic activity [50]
Muricatetrocin AAGESeed and/or leafCytotoxic activity [17, 50]
Muricatetrocin BAGESeed
Gigantetrocin BAGESeed
cis-AnnonacinAGESeedCytotoxic activity [85]
cis-Annonacin-10-oneAGESeed
cis-GoniothalamicinAGESeed
ArianacinAGELeaf
JavoricinAGELeaf
HexaneExtractLeafDoses: 10, 20, 40, and 80 μg/mL, (72 hr)Significantly reduced cell proliferation in cancer cells [26]
Ethyl acetateExtractLeafDoses in vitro: 10, 20, 40, and 80 μg/mL [26]; 0.62, 1.25, 2.5, 5, 10, 20, 40, and 80 μg/mL [25]; (72 hr) [26]. Doses in vivo: 250 or 500 mg/kg into male Sprague-Dawley rats [25].Induced significant cytotoxic effects, cell cycle arrest at G1 phase, and apoptosis. Treatment also caused excessive accumulation of ROS followed by disruption of MMP, cytochrome c leakage, and activation of the initiator and executioner caspases in cancer cells. In addition, it upregulated Bax and downregulated Bcl-2 proteins. Furthermore, treatment conspicuously blocked the migration and invasion of cancer cells [26]. In rats treated with azoxymethane to induce colorectal carcinogenesis. This extract reduced colonic aberrant crypt foci formation by 72.5% in vivo via downregulation of PCNA and Bcl-2 proteins and upregulation of Bax protein as well as an increase in the levels of enzymatic antioxidants and a decrease in the malondialdehyde level of the colon tissue homogenates, suggesting the suppression of lipid peroxidation [25]
MethanolExtractLeafDoses: 10, 20, 40, and 80 μg/mL and (72 hr)Significantly reduced the cell proliferation in cancer cells [26]
HCT-116HexaneExtractLeafDoses: 10, 20, 40, and 80 μg/mL and (72 hr)
Ethyl acetateExtractLeafDoses: 10, 20, 40, and 80 μg/mL and (72 hr)In cancer cells, induced significant cytotoxic effects, cell cycle arrest at the G1 phase, and apoptosis as well as excessive accumulation of ROS followed by disruption of MMP, cytochrome c leakage, and activation of the initiator and executioner caspases. It also upregulated Bax and downregulated Bcl-2 protein. Furthermore, treatment conspicuously blocked the migration and invasion of cancer cells [26]
MethanolExtractSeedDoses: 10, 20, 40, and 80 μg/mL and (72 hr)Significantly reduced cell proliferation in cancer cells [26]
HCT116 (p53+/+)MethanolExtractPericarpCytotoxic activity [24]
MethanolExtractLeaf
MethanolExtractSeed
HCT116 (p53/)MethanolExtractPericarp
MethanolExtractLeaf
MethanolExtractLeaf
———EthanolicExtractLeaf300 mg/kg into Wistar albino ratsShowed potent anticancer activity through apoptosis and reduction of aberrant crypt foci formation [20]
EthanolExtractLeaf100 mg/kg body weight/4 weeks are administrated into Wistar ratsIn a rat model of Cycas-induced colorectal carcinogenesis, protected against some early events as monitored by histology and protein expression [140]
COLO-20596% Ethanol [112] or ethanol soluble fraction leaf water extract contains 0.36% acetogenin (w/w) or 3.6 mg/g, and a 10 g water extract is equivalent to a 2 g ethanolic fraction [94].ExtractLeafDoses in vitro: 400, 200, 100, 50, 25, 12.5, 6.25, 3.125, and 1.5625 mg/L, (48 hr) [112]. Ex vivo, the colorectal cancer patients consumed either 300 mg of the extract, or maltose as a placebo, in the form of a capsule after breakfast [94].Enhanced proapoptotic caspase-3 marker activity [112]. Ex vivo and clinical studies showed higher cytotoxicity in the supplemented group compared with the placebo group [94]
DLD-1Ethanol soluble fraction leaf water extract contains 0.36% acetogenin (w/w) or 3.6 mg/g, and a 10 g water extract is equivalent to a 2 g ethanolic fraction.ExtractLeafPatients consumed either 300 mg of extract, or maltose as a placebo, in the form of a capsule after breakfast.Ex vivo and clinical studies showed higher cytotoxicity in the supplemented group compared with the placebo group [94]
HTC-8(+)-(3S,6S,7R,8S)-Periconone AFungal strain ExtractLeafDoses: 0.01–10 μmol/mlCytotoxic activity [38]
(−)-(1R,4R,6S,7S)-2-Caren-4,8-olideFungal strain ExtractLeaf
Lung cancerA549Annomuricin AAGELeafCytotoxic activity [17]
Annomuricin BAGELeaf
Annomuricin CAGELeaf—–—Cytotoxic activity [86]
Muricatocin CAGELeaf
Annomuricin EAGELeafCytotoxic activity [16]
MuricapentocinAGELeaf
AnnomutacinAGELeafCytotoxic activity [43]
(2,4-cis)-10R-Annonacin-A-one + (2,4-trans)-10R-annonacin-A-oneAGEsLeaf
AnnohexocinAGEsLeafSignificant cytotoxic activity [34]
Muricatocin AAGELeafCytotoxic activity [44]
Muricatocin BAGELeaf
Annopentocin AAGELeafCytotoxic activity [32]
Annopentocin BAGELeaf
Annopentocin CAGELeaf
cis-Annomuricin-D-one + trans-annomuricin-D-oneAGEsLeaf
Murihexocin AAGELeafSignificant cytotoxic activity [15]
Murihexocin BAGELeaf
Murihexocin CAGESeedCytotoxic activity [47]
MuricoreacinAGESeed
MuricatacinAGESeedCytotoxic activity [48]
IsoannonacinAGESeedCytotoxic activity [49]
Isoannonacin-10-oneAGESeed
GoniothalamicinAGESeed and/or leaf
GigantetrocinAGESeed and/or leaf
Gigantetrocin AAGESeedCytotoxic activity [17, 50]
Muricatetrocin AAGESeed and/or leaf
Muricatetrocin BAGESeed
Gigantetrocin BAGESeed
cis-AnnonacinAGESeedCytotoxic activity [85]
cis-Annonacin-10-oneAGESeed
cis-GoniothalamicinAGESeed
ArianacinAGELeafIC50 = 4.7 × 10−3μg/mL
JavoricinAGELeaf
Ethyl acetate componentExtractLeafDoses: 1.56, 3.12, 6.25, 12.5, 25, 50, and 100 μg/mL; IC50: 5.09 ± 0.41 μg/mL (72 hr)Selective cytotoxic effect against cancer cells and significant lactate dehydrogenase leakage and phosphatidylserine externalization demonstrated by fluorescence analysis. Treatment also elevated ROS formation, while attenuating MMP via upregulation of Bax and downregulation of Bcl-2. This was accompanied by cytochrome c release to the cytosol, which triggered activation of caspase-9 and caspase-3. These proapoptotic effects were accompanied by cell cycle arrest at the G0/G1 phase and suppression of NF-κB translocation from the cytoplasm to the nucleus [31]
HexaneExtractLeafDoses: 1.56, 3.12, 6.25, 12.5, 25, 50, and 100 μg/mL; Significantly reduced cell proliferation in cancer cells [31]
MethanolExtractLeafDoses: 1.56, 3.12, 6.25, 12.5, 25, 50, and 100 μg/mL;
(+)-(3S,6S,7R,8S)-Periconone AFungal strain ExtractLeafDoses: 0.01–10 μmol/mLCytotoxic activity [38]
(−)-(1R,4R,6S,7S)-2-Caren-4,8-olideFungal strain ExtractLeaf
H-460EthanolExtractTree/LeafCytotoxic activity [95]
Ethanol (95%)ExtractPericarpCytotoxic activity [45]
NCI-H292MethanolExtractPericarpIC50: 24.94 ± 0.74 μg/mLAntiproliferative and cytotoxic activities towards cancer cells [113]
Leukemia (hematological malignancies)U-937Annonacin AAGEPericarpDoses: 0.1, 0.46, and 1.0 mg/mLCytotoxic activity [46]
Annomuricin AAGEPericarp
MethanolExtractPericarp
HexaneExtractLeaf
Ethyle acetateExtractStem
Ethyle acetateExtractStemCytotoxic activity [131]
Ethyle acetateExtractStem and/or 28.1 ± 13.0 μg/mLCytotoxic activity [33]
MethanolExtractStem and/or 38.5 ± 8.6 μg/mL
HexaneExtractStem and/or 15.7 ± 5.1 μg/mL
K562EthanolExtractLeafDoses in vitro: 0.625 mg/mL, 1.25 mg/mL, 2.5 mg/mL, and 5.0 mg/mL [19]; 0.1–10 mg/mL [96]; [96]. Dose in vivo: 0.5 g/kg into albino mice [96].Showed cytotoxicity in vitro [19] and in vivo [96]. This was accompanied in vitro by significantly increased caspase-3 activity. Induction of apoptosis was confirmed by a terminal deoxynucleotidyl transferase-mediated dUTP nick-end labelling (TUNEL) assay [19]
HL-60EthanolExtractRootInduced apoptosis through loss of MMP and inhibited proliferation via G0/G1 cell cycle arrest [27]
EthanolExtractFruit/pericarp
EthanolExtractLeaf
CCRF-CEMMethanolExtractSeedInduced cytotoxic, apoptosis, and cell cycle arrest [24]
MethanolExtractLeaf
MethanolExtractSeed
CEM/ADR5000MethanolExtractPericarp
MethanolExtractLeaf
MethanolExtractLeaf
Renal cancerA498Annomuricin EAGELeafCytotoxic activity [16]
MuricapentocinAGELeaf
AnnohexocinAGELeafCytotoxic activity [34]
Annopentocin AAGELeafCytotoxic activity [32]
Annopentocin BAGELeaf
Annopentocin CAGELeaf
cis-Annomuricin-D-one + trans-annomuricin-D-oneAGEsLeaf
Murihexocin AAGELeafSignificant cytotoxic activity [15]
Murihexocin BAGELeaf
Murihexocin CAGELeafCytotoxic activity [47]
MuricoreacinAGELeaf
Pancreatic cancerPACAAnnomuricin EAGELeafCytotoxic activity [16]
MuricapentocinAGELeaf
PACA-2AnnohexocinAGELeafSignificant cytotoxic activity [34]
Annopentocin AAGELeafCytotoxic activity [32]
Annopentocin BAGELeaf
Annopentocin CAGELeaf
cis-Annomuricin-D-one + trans-annomuricin-D-oneAGEsLeaf