Review Article

Propolis: A Complex Natural Product with a Plethora of Biological Activities That Can Be Explored for Drug Development

Table 8

Antitumoral activity of propolis and its chemical constituents.

OriginPropolis type/plant sourceType of extract/isolated compound(s)Species/cellsEffectReferences

ThailandPropolis from stingless bee Trigona laeviceps Hexane extract Colon (SW620), breast (BT474), hepatic (Hep-G2), lung (Chago), and stomach (Kato-III) cells
Normal cell lines: liver (CH-liver) and fibroblast (HS-27)
High antiproliferative activity against the five cancer cell lines and low cytotoxic activity on the normal cell lines[5]

PolandEuropean propolis/Populus nigra and some species of Betula alba, Alnus glutinosa, Aesculus hippocastanum, and Fagus sylvatica PEEHuman malignant melanoma cell line Me45; colorectal cancer cell line HCT 116Inhibition of cell growth and reduction of cell size of the tested cancer cells[154]

SynthesizedCharacteristic of propolis from the Pacific region, Thailand, Africa, Australia, and BrazilPrenylated flavanones Prostate cancer cell lines PC-3 and DU-145
Human hepatoma cell line Hep-3B
Induction of a more potent cytotoxicity against the PC-3 cell line than 5-flurouracil; induction of apoptosis[45]
Characteristic of European propolisCAPEC6 cell line established from a glioma generated by intravenous exposure of male Wistar rats to N-nitrosomethylurea BALB/c-nu miceInhibition of C6 glioma cells growth; increase in the percentage of cells in the G0/G1 phase, and decrease in the protein level of hyperphosphorylated pRb; increase in cyclin dependent kinase inhibitors p21, p27, and p16; decrease in tumor growth in xenografts, reduction of the number of mitotic cells and proliferating cell nuclear antigen- (PCNA-) positive cells in C6 glioma[206]
HL-60 cell lineInduction of apoptosis by activation of caspase-3, downregulation of Bcl-2, and upregulation of Bax[207]

BrazilCharacteristic of Brazilian propolisDrupanin, baccharin ((E)-3-prenyl-4-(2,3-dihydrocinnamoyloxy) cinnamic acid) and artepillin C (isolated from PEEs of propolis)Human leukemia cell line HL-60, colon cancer cell line SW480Inhibition of cells growth; promotion of morphological changes and nucleosomal DNA fragmentation (artepillin C > baccharin > drupanin)[208]
Red propolis/D. ecastaphyllum Methanolic extractHuman pancreatic cancer cells (PANC-1)Killing 100% of PANC-1 cells in the nutrient-deprived condition[157]
Green propolis/B. dracunculifolia PEEDU145 and PC-3 cell lines, telomerase-immortalized primary human prostate cancer-derived cell (RC-58T/h/SA#4), and primary human prostate epithelial cells (PrEC)Inhibition of human prostate cancer cells proliferation by regulating the protein expression of cyclin D1, B1 and cyclin dependent kinase (CDK), p21[158]
Green propolis/B. dracunculifolia Baccharin, beturetol, kaempferide, isosakuranetin, and drupanin (isolated from PEE)Human embryonic kidney 293 (HEK293) cell, HCT116 cell lineInhibition of HIF-1α, glucose transporter 1, hexokinase 2, and vascular endothelial growth factor A (VEGF-A) expression; exhibiting anti-angiogenic effects in the chick chorioallantoic membrane[209]
Green propolis/B. dracunculifolia PEEHUVECs cellsInduction of apoptosis in tube-forming endothelial cells through the inactivation of the survival signal ERK1/2 and by the activation of caspase-3[175]
Green propolis/B. dracunculifolia PWEFemale Wistar ratsInhibition of angiogenesis in N-butyl-(-4-hydroxybutyl) nitrosamine- (BBN-) induced rat bladder cancer[210]
Red propolis/D. ecastaphyllum PEEHuman immortalized endothelial-like cell line EA.hy926, renal cell carcinoma cell line RCC4, and mouse embryonic stem cell line CGRReduction of migration and sprouting of endothelial cells and attenuation of new blood vessels formation; decrease in the differentiation of embryonic stem cells into CD31 positive cells; decrease in HIF1-α protein accumulation which attenuates VEGF gene expression, increases the von Hippel-Lindau- (pVHL-) dependent proteasomal degradation of HIF1-α, and downregulates Cdc42 protein expression[211]

BrazilGreen propolis/B. dracunculifolia PEEHuman umbilical vein endothelial cells (HUVECs), NF1-deficient MPNST (S-462), and NF2-deficient schwannoma (HEI-193) cell lines
Female nu/nu mice
Blocking PAK1 signaling selectively, without affecting AKT; suppressing almost completely the growth of human neurofibromatosis tumor xenografts in mice [156]
SynthesizedCharacteristic of Brazilian
Artepillin C

BrazilGreen propolis/B. dracunculifolia PEEHUVECs
Female ICR mice
Reduction of the number of newly formed vessels in vivo
Suppression of HUVECs proliferation and inhibition of tube formation
Purchased: Wako Pure Chemicals Industries (Osaka, Japan)Characteristic of Brazilian propolisArtepillin C

BrazilGreen propolis/B. dracunculifolia PEELNCaP cell lineSensitizing TRAIL-resistant LNCaP cells to TRAIL-induced apoptosis
Induction of a significant disruption of
Enhancing the expression of TRAIL-R2 and decreasing the activity of NF-κB
Artepillin C, quercetin, kaempferol, and p-coumaric acid strongly cooperating with TRAIL to induce apoptosis
Purchased: Alexis Biochemicals (San Diego, CA, USA)Characteristic of Brazilian propolisQuercetin, kaempferol, and p-coumaric acid
Purchased: Wako Pure Chemicals (Osaka, Japan)Artepillin C
BrazilRed propolis/D. ecastaphyllum PEEMCF-7 cell lineReducing cell viability through induction of mitochondrial dysfunction, caspase-3 activity, and DNA fragmentation and increase in expression of CCAAT/enhancer-binding protein homologous protein (CHOP) [212]
Purchased: Api Co. Ltd., Gifu, JapanCharacteristic of European propolisCAPE

Purchased: Sigma Aldrich Co.Characteristic of European propolisCAPELNCaP 104-S, DU-145, and PC-3 cell lines
Male BALB/c mice
Suppressing the growth of LNCaP, DU-145, and PC-3 and inhibiting the tumor growth of LNCaP xenografts, possible inhibition of p70S6K and some Akt signaling networks[161]
PC-3 cell lineSuppressing proliferation, colony formation, and cell cycle progression, decrease in protein expression of cyclin D1, cyclin E, SKP2, c-Myc, Akt1, Akt2, Akt3, total Akt, mTOR, and Bcl-2, Rb, as well as phosphorylation of Rb, ERK1/2, Akt, mTOR, GSK3a, GSK3b, and PDK1, and increase in KLF6 and p21Cip1 protein expression[213]
Breast cell lines MDA-MB-231, MCF-7, MCF-10A, and MCF-12A Bovine capillary endothelial (BCE) cells
Female (Ncr-nu-nu) mice
Inhibition of in vitro and in vivo MCF-7 and MDA-MB-231 tumor growth without much effect on normal mammary cells; induction of cell cycle arrest and apoptosis by downregulation of Bcl-2 proteins; reduction of NF-κB and mdr-1 gene expression and suppression of VEGF production by MDA-231 cells and formation of capillary-like tubes by endothelial cells[162]
Breast cancer cell lines MDA-MB-231, MCF-7, and SKBR3Promotion of an accumulation of acetylated histone proteins in MCF-7 (ER+) and MDA-MB-231 (ER−/PR−/Her2−); decrease of ER and PR in MCF-7 cells and upregulation of ER and decrease of EGFR in MDA-MB-231 cells; reduction of Her2 protein in SKBR3 (Her2+) cells[163]
Human oral squamous cell carcinoma TW2.6Suppression of cell proliferation and colony formation; decrease of G1 phase cell population, increase of G2/M phase cell population; induction of apoptosis; decrease of Akt, Akt1, Akt2, Akt3, phospho-Akt Ser473, phospho-Akt Thr 308, GSK3β, FOXO1, FOXO3a, phospho-FOXO1 Thr24, phospho-FoxO3a Thr32, NF-κB, phospho-NF-κB Ser536, Rb, phospho-Rb Ser807/811, Skp2, and cyclin D1; and increase of cell cycle inhibitor p27Kip[214]
MDA-MB-231 cell lineInhibition of cancer stem cells self-renewal, progenitor formation, and clonal growth and decrease of CD44 levels[164]
Human hepatocellular carcinoma cell line SK-Hep1Suppression of the adhesion and invasion potential of the cells by inhibiting completely the expression of MMP-2 and metalloproteinase-9 (MMP-9) and the NF-κB[172]
Human fibrosarcoma cell line HT1080Decrease of MMP and tissue inhibitor metalloproteinase-2 (TIMP-2) mRNA levels; downregulation of MMP-2 and MMP-9 expression; inhibition of MMP-2 activity; decrease of invasion, motility, cell migration, and colony formation[215]

TurkeyMediterranean propolis/Populus spp., Eucalyptus spp., and Castanea sativa PEEMCF-7 cell lineIncrease of apoptosis through the caspase pathway[216]

IraqEuropean propolis/Populus nigra PWEHL-60 cell line, colon cancer cell HCT-116
Female athymic Fox N1-nu/nu mice
Inhibition of HL-60 cells proliferation and induction of apoptosis by downregulating Bcl-2 protein and upregulating Bax; inhibition of HCT-116 cells colony formation potential and promotion of necrotic changes; decrease of mitotic cells and increase of p53 and Ki-67 expression in HCT-116 tumor-bearing mice[13]

IranEuropean propolis/Poplar spp., Ferula ovina PEEMale Wistar ratsDecrease of tumour incidence, number of lesions, structural abnormalities, and beta-catenin and induction of proapoptotic Bax expression and reduction of antiapoptotic Bcl-2 expression[165]

Provided by Wako Pure Chemicals (Osaka, Japan)Characteristic of Brazilian propolisArtepillin C LNCaP cell lineInduction of caspase-8 and caspase-3 activation and disruption of mitochondrial membrane potential by a cotreatment with TRAIL and artepillin C[169]

PurchasedCharacteristic of European propolisCAPEMCF-7 cell lineInduction of apoptosis via Fas signal; induction of Bax protein and activation of caspases and MAPK family proteins p38 and JNK[217]

Purchased: Calbiochem (San Diego, CA, USA)Characteristic of European propolisCAPELymphoblastoid cell line PL104Induction of apoptosis through phosphatidylserine (PS) exposure and nuclear fragmentation
Increase of sub-G1 DNA content; downregulation of surviving and Bcl-2 expression and increase of BAX proteins levels; induction of mitochondrial membrane potential (ψm) collapse; induction of cytochrome c release from mitochondria and induction of caspases 3, 7, and 9 activation

China;European propolis/Populus nigra PEEHUVECs Inhibition of VEGF expression [179]
Purchased: Api Co. Ltd. (Gifu, Japan)Characteristic of European propolisCAPE

Korea;European propolis/Populus nigra PEEFertilized chicken eggs
Calf pulmonary arterial endothelial (CPAE) cells
Inhibition of angiogenesis in chick embryo chorioallantoic membrane and inhibition of CPAE cells proliferation [176]
SynthesizedCharacteristic of European propolisCAPE

Portugal: (Serra de Bornes and Fundão);European propolis/Populus nigra Methanolic extractNormal and cancerous renal cells derived from human renal cell carcinoma patients, human renal carcinoma cell line A-498Inhibition tumor cells growth exhibiting selective toxicity against malignant cells compared to normal cells[64]
(Anga do Heroísmo, Azores)PEE and hexane, chloroform, and residual ethanol extract fractions obtained from the PEEHuman colorectal adenocarcinoma cell line HCT-15All the samples exhibiting cytotoxic effect against tumor cells; chloroform fraction decreasing cell viability, promoting cell death, and disturbing tumor cell glycolytic metabolism[218]