Three 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]
A 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 time
Her 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
———
Extract
Leaf
Doses: 5, 25, 50, or 100 μg/mL; in vitro. In addition 200 mg/kg/35 week injected into the back of athymic mice in vivo
Inhibited 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]
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]
Significantly reduced cell proliferation in cancer cells [26]
Ethyl acetate
Extract
Leaf
Doses 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]
Methanol
Extract
Leaf
Doses: 10, 20, 40, and 80 μg/mL and (72 hr)
Significantly reduced the cell proliferation in cancer cells [26]
HCT-116
Hexane
Extract
Leaf
Doses: 10, 20, 40, and 80 μg/mL and (72 hr)
Ethyl acetate
Extract
Leaf
Doses: 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]
Methanol
Extract
Seed
Doses: 10, 20, 40, and 80 μg/mL and (72 hr)
Significantly reduced cell proliferation in cancer cells [26]
Showed potent anticancer activity through apoptosis and reduction of aberrant crypt foci formation [20]
Ethanol
Extract
Leaf
100 mg/kg body weight/4 weeks are administrated into Wistar rats
In a rat model of Cycas-induced colorectal carcinogenesis, protected against some early events as monitored by histology and protein expression [140]
COLO-205
96% 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].
Extract
Leaf
Doses 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-1
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.
Extract
Leaf
Patients 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]
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]
Hexane
Extract
Leaf
Doses: 1.56, 3.12, 6.25, 12.5, 25, 50, and 100 μg/mL;
Significantly reduced cell proliferation in cancer cells [31]
Methanol
Extract
Leaf
Doses: 1.56, 3.12, 6.25, 12.5, 25, 50, and 100 μg/mL;
Doses 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-60
Ethanol
Extract
Root
Induced apoptosis through loss of MMP and inhibited proliferation via G0/G1 cell cycle arrest [27]
Ethanol
Extract
Fruit/pericarp
Ethanol
Extract
Leaf
CCRF-CEM
Methanol
Extract
Seed
Induced cytotoxic, apoptosis, and cell cycle arrest [24]
Powder without binders or fillers (capsule contents is suspended in DMSO (100 mg/mL DMSO)
Extract
Leaf
Doses: 10–200 μg/mL.
Induced cytotoxicity and necrosis by inhibiting cellular metabolism. In addition, it downregulated the expression of molecules related to hypoxia and glycolysis (i.e., HIF-1α, NF-κB, GLUT1, GLUT4, HKII, and LDHA) in cancer cells. Also, the motility of pancreatic cancer cells was decreased [28]
CD18/HPAF
DMSO in vitro and H2O in vivo
Extract
Leaf
Doses: 10–200 μg/mL, IC50 = 73 μg/mL in vitro. 50 mg/kg/35 days injected orthotopically in the pancreas of athymic nude mice
Induced cytotoxicity and necrosis and inhibited cellular metabolism. In addition, it downregulates the expression of molecules related to hypoxia and glycolysis (i.e., HIF-1α, NF-κB, GLUT1, GLUT4, HKII, and LDHA) in cancer cells. After treatment, the motility of pancreatic cancer cells was decreased. It also caused 59.8% growth inhibition of pancreatic tumor induced in mice orthotopically implanted with CD18/HPAF cells [28]
Capan-1
Hexane
Extract
Seed
Inhibited cell proliferation and induced mild cytotoxicity in cancer cells [92]
DMSO
Commercialized Extract
Seed
Hepatic cancer
Hep G2
Muricin H
AGE
Seed
Exhibited significant activity in in vitro and cytotoxic assays against human hepatoma cell line [81]
