Propolis: An update on its chemistry and pharmacological applications

Hossain, Rajib; Quispe, Cristina; Khan, Rasel Ahmed; Saikat, Abu Saim Mohammad; Ray, Pranta; Ongalbek, Damira; Yeskaliyeva, Balakyz; Jain, Divya; Smeriglio, Antonella; Trombetta, Domenico; Kiani, Roghayeh; Kobarfard, Farzad; Mojgani, Naheed; Saffarian, Parvaneh; Ayatollahi, Seyed Abdulmajid; Sarkar, Chandan; Islam, Mohammad Torequl; Keriman, Dılhun; Uçar, Arserim; Martorell, Miquel; Sureda, Antoni; Pintus, Gianfranco; Butnariu, Monica; Sharifi-Rad, Javad; Cho, William C.

doi:10.1186/s13020-022-00651-2

Chinese Medicine

Table 7 Anticancer properties of propolis ethanol, water, methanol and hydroalcholic extracts (EE, WE, ME and HAE, respectively) and their isolated compounds

From: Propolis: An update on its chemistry and pharmacological applications

Compound/extract	Model	Concentration/dose	Study type	Mechanism	Origin	References
Hyperibone A	HeLa tumor cells	IC₅₀ = 0.18 µM	In vitro	Cytotoxic	Brazil	[95]
Nemorosone	HeLa tumor cells	IC₅₀ = 3.3 µM	In vitro	Cytotoxic	Cuba	[95]
Luteolin	Human colon cancer (HCT-116)	IC₅₀ = 115.68 μM	In vitro	Cytotoxic/apoptosis	Serbia	[96]
Luteolin	Human triple negative breast cancer (MDA-MB-231) cell lines	IC₅₀ = 66.86 μM	In vitro	Cytotoxic/apoptosis
Myricetin	Human triple negative breast cancer (MDA-MB-231) cell lines	IC₅₀ = 114.75 μM	In vitro	Inhibition of cell growth and apoptosis
Galangin	Human colon cancer and human triple negative breast cancer cell lines	IC₅₀ = 50 μM	In vitro	Apoptosis
EE	glioblastoma cells cancer line	IC50 = 92.2 µg/mL	In vitro	Cytotoxic	Mexico	[98]
(7′′R)-8-[1-(4′-Hydroxy-3′-methoxyphenyl) prop-2-en-1-yl] galangin	PANC-1 humanpancreatic cell line	IC₅₀ = 4.6 μM	In vitro	Apoptosis-like morphological changes/Cytotoxic	Mexico	[97]
Chrysin, pinobanksin, pinobanksin-3-O-propanoate, pinobanksin-3-O-butyrate, pinobanksin-3-O-pentanoate, pinobanksin-3-O-hexanoate	B-cell lymphoma cell line	IC₅₀ = 49.1 µM; 52.1 µM; 67.0 µM; 49.9 µM; 51.3 µM; 76.6 µM	In vitro	Antiproliferative activity through apoptotic induction	Sonaran	[99]
Turkish propolis EE	Human adenocarcinomic alveolar basal epithelial (A549) cancer	IC₅₀ = 31.7 µg/mL	In vitro	Cell cycle arrest (G₁ phase), induction of endoplasmic reticulum stress, caspase activity, and apoptosis; decrease ofmitochondrial membrane potential	Turky	[100]
Turkish EE	human normal foreskin fibroblast cells	IC₅₀ = 76.9 µg/mL	In vitro	Cytotoxic activity	Turky	[100]
Turkish EE	Human adenocarcinomic alveolar basal epithelial (A549) cancer	31.7 and 57.1 µg/mL	In vitro	Increase of caspase activity; decrease of mitochondrial membrane potential; up-regulation CHOP mRNA expression; cell cycle arrest (G₁phase)—apoptosis	Turky	[100]
EE	HCT 116 Colon Cancer and Me45 Malignant Melanoma Cells	IC₅₀ = 100 µM	In vitro	Anti-proliferative and pro-apoptotic Effect	Poland
Propolone A-B	Ovarian cancer cell line	LC₅₀ = 19.1 µM and 29.9 µM	In vitro	Anti-proliferative	Brazil	[102]
Novel 2-phenoxychromone; 3-O-methylquercetin; 3,6,4′-trimethoxychrysin; 3,6-dimethoxyapigenin	DLD-1 (human colon cancer),	IC₅₀ = 65.8; 16.2; 17.1; 31.0 μM	In vitro	Anti-proliferative effect; cell growth inhibition	Brazil	[103]
	MCF-7 (human breast cancer) and	IC₅₀ = 174.4; 16.7; 50.5; 41.9 μM
	A549 (human lung cancer) cancer cell lines	IC₅₀ = 81.9; 34.2; 19.9; 47.0 μM
Sonoran Desert EE	Cancerous cell line M12.C3.F6 (murine B cell lymphoma)	IC₅₀ = 22.4 μM	In vitro	Antiproliferative	Sonoran Desert	[104]
Caffeic acid and pinocembrin	Human colorectal adenocarcinoma DLD-1 cells	IC₅₀ = 200 μM	In vitro	Antiproliferative	New Zealand	[105]
Ardabil EE and quercetin	Mouth epidermoid carcinoma (KB) cell line	IC₅₀ = 40 mM and 195 μM	In vitro	Cell proliferation inhibition	Iran	[106]
Ardabil EE and quercetin	Skin squamous cellcarcinoma (A431) cell line	IC₅₀ = 98 μM, and 195 μM	In vitro	Cell proliferation inhibition	Iran	[106]
EE from stingless bees Tetragoniscafiebrigi	K562 erythroleukemia cells	IC₅₀ = 250 and 500 μg/mL	In vitro	Necrosis	Brazil	[107]
Brazilian red EE	Colon cancer cell lines (human colorectal adenocarcinoma and human colorectal carcinoma)	IC₅₀ = 75.15 and 70.81 μg/mL	In vitro	Antitumor activity	Brazil	[108]
p-Coumaric acid	Four triple-negative breast cancer cell lines (BT-20, BT-549, MDA-MB-231, and MDA-MB-436 cells)	IC₅₀ = 17.02, 13.94, 22.85, and 23.55 µM	In vitro	Cytotoxic; decrease of cell viability	Brazil	[109]
( −)-Epigallocatechin-3-gallate	BT-20, BT-549, MDA-MB-231, and MDA-MB-436 cells,	IC₅₀ = 20.10, 19.16, 24.97 and 18.16 µM	In vitro	Cytotoxic; decrease of cell viability	Brazil	[109]
EE	AGS human gastric cancer cell	60, 30, and 15 µg/mL	In vitro	Cell growth and proliferation inhibition	Iran	[110]
	Human breast cancer, colon adenocarcinoma, epithelial colorectal adenocarcinoma, murine melanoma	50 and 100 μg/mL	In vitro	Cytotoxic/apoptosis	India	[111]
	HeLa cervical cancer cells	IC₅₀ = 80.96 μg/mL	In vitro	Cytotoxic/anti-proliferative effect	Thailand	[112]
EE	Human colon carcinoma cell lines CaCo2	IC₅₀ = 50 μg/ml	In vitro	Growth inhibitory activity by apoptosis	China	[113]
	Human colon carcinoma cell lines CaCo2	20 μg/ml	In vitro	Decrease of cells in G1, S and G2-M phases, modulation of p53 protein	China	[113]
	HCT116	38.9 μg/ml	In vitro	Growth inhibitory activity by apoptosis	Brazil	[113]
EE	Human colon carcinoma cell lines CaCo2	> 50	In vitro	Growth inhibitory activity by apoptosis	Brazil	[113]
Turkish EE	PC-3 cell line	IC₅₀ = 20.7 μg/mL	In vitro	Cytotoxic activity		[114]
Flavonoids and phenolic acid	Human tongue squamous cell carcinoma cell line	25 and 50 μg/mL	In vitro	Activation of caspases-3, -8 and -9		[115]
	Human rectal and colon cancer cell	10 μg/mL	In vitro	Proliferation inhibition		[116]
	Human U87MG glioblastoma cell	TMZ (10–100 μM), EE (10-100 μg/mL)	In vitro	Glioblastoma cell growth inhibition NF-κB activity down-regulation		[117]
Artepillin C	HT1080 (fibrosarcoma), A549 (lung carcinoma) and U2OS (osteosarcoma) human cell lines	IC₅₀ = 275 µM	In vitro	Abrogation of mortalin-p53 complexes causing the activation of p53	Brazil	[118]
Caffeic acid phenethyl ester	Human cancer cells, SKOV3 (ovarian carcinoma), HT1080 (fibrosarcoma), A549 (lung carcinoma), HeLa (cervical carcinoma), U2OS (osteosarcoma), MCF7 and MDA-MB-231 (breast adenocarcinoma	50 µM	In vitro	Down-regulation of mortalin and up-regulation of GADD45α and p53 tumor suppressor proteins	New Zealand	[119]
EE	MCF7 cells	IC₅₀ = 62.24 μg/mL	In vitro	Proliferation inhibition		[120]
DMEP-A-C	head and neck squamous cell carcinoma (HNSCC) cell lines	IC₅₀ = 76.33 µg/mL	In vitro	Cytotoxic activity; metastatic proliferation inhibition		[121]
P. droryana propolis	the K562 erythroleukemia tumour line	IC₅₀ = 0.38 mg/mL	In vitro	Cell viability decrease		[122]
Chyrsin	MDA-MB-231breast cancer cell	40 μM and 60 μM	In vitro	Up-regulation of p21(waf1/cip1) gene expression and inhibition of histone deacetylase 8	China	[123]
Chyrsin	xenograft animalmodel	90 mg/Kg/day per os		Cell growth suppression	China	[123]
Pinobanksin-3-acetate	human colon cancer	IC₅₀ = 163.61 μg/mL	In vitro	proliferation inhibition and apoptosis induction through up-regulation and down-regulation of multiple genes involved in cell apoptosis, cytokinetics, colorectal carcinogenesis, Wnt, and calcium signaling		[124]
ME	HML cells U937	300–500 μg/mL	In vitro	Dose-dependent decrease of Bcl-2 expression, no changes in Bax expression, apoptosis		[125]
Liquiritigenin, formononetin, medicarpin, biochanin A, retusapurpurin	Carcinoma BCL- 5637	25, 50 and 100 μg/mL	In vitro	Increase of Bax/Bcl-2 ratio levels	Brazil	[126]
EE	Prostate Cancer cell lines PC-3	IC₅₀ = 38.48 μg/mL	In vitro	Slight increase on Bax mRNA	Egypt	[127]
EE	Human lung carcinoma cell line	1/4 IC₅₀₌ 17.29 μg/mL	In vitro	Decrease of mitochondrial membrane potential by overexpression of pro-apoptotic genes (Bax and Noxa) and decrease of the Anti-apoptotic gene Bcl-XL	Brazil	[128]
WE^°	HL-60 and HCT-116 cell lines	25 μg/mL	In vitro	Increase of Bax	Iraq	[129]
EE	Breast Cancer lines MCF-7	10 and 20 μg/mL	In vitro	Increase of Bax mRNA and decrease ofBcl-2 mRNA	Brazil	[130]
EE	HEp-2 human laryngeal carcinoma cell	1/4 IC₅₀ = 14 and 16 μg/mL	In vitro	Down-regulation of Bcl-2 and Bcl-XL mRNA; Up-reguation of Bax; apoptosis	Brazil	[131]
ME	HML cells U937	100, 300 and 500 μg/mL	In vitro	Caspase-3 activation	Japan	[125]
EE	Breast Cancer lines MCF-7 and MDAMB- 231	50, 100 and 200 μg/mL	In vitro	Caspase-3 activation	Chinese	[132]
EE	HeLa	Nan: 125 μg/mL Chiang Mai: 250 μg/mL	In vitro	Caspase-3 activation	Thailand	[133]
EE	Human tongue carcinoma cell line (CAL-27)	200 μg/mL	In vitro	Caspase − 3,-8 and -9 activation	Poland	[115]
EE	Breast Cancer lines MCF-7	63, 125 and 250 μg/mL	In vitro	Activation of caspase-6 than caspases-8 and 9	Turkey	[134]
EE	Breast Cancer lines MCF-7	20 μg/mL	In vitro	Caspase-3 activation	China and Brazil	[130]
	HEp-2 human laryngeal carcinoma cell	IC₅₀ = 80 μg/mL	In vitro	Apoptosis due to ROS generation and caspase-3 activation	Brazil	[135]
EE	Human lung carcinoma cell line A549	35 μg/mL	In vitro	Mitochondrial membrane potential decrease and caspase activity increase	Turkey	[100]
EE	LNCaP prostate cancer cells	25–50 μg/mL	In vitro	Up-regulation of TRAIL-R2		[136, 137]
Cardol	SW620 human colorectal cancer cell line	IC₅₀ = 4.51 ± 0.76 μM	In vitro	Increase of caspase-3 and -9 activityand PARP; apoptosis; mitochondrial membrane potential decrease; antiproliferative effect; G₀/G₁ cell cycle arrest	Indonesian propolis	[138]
EE	HUVECs	6.25–25 μg/mL	In vitro	Apoptosis in tube-forming endothelial cells through inactivation of survival signal ERK1/2	Chinase	[139]
EE	HUVECs	6.25–25 μg/mL	In vitro	Decrease of PC-PLC activity, p53 and ROS levels	Brazil	[140]
EE	HUVECs	3.13–25 μg/mL	In vitro	Angiogenesis suppression through inhibition of tube formation and proliferation; decrease of the number of newly formed vessels	Korean	[141]
HAE	HUVECs	100–200 μg/mL; 50–450 mg/Kg	In vitro	Inhibition of the tube-like structure formation (tubulogenesis)		[142]
EE	Carcinoma BCL-5637	25 and 50 μg/mL	In vitro	Cell migrationinhibition	Brazil	[126]
EE	Breast Cancer line MDA-MB -231	25, 50, 100 and 200 μg/mL	In vitro	Cells migration inhibition	China	[132]
EE	Glioblastoma multiforme cell line U87MG	30 μg/mL	In vitro	Cell migration inhibition	Poland	[143]
EE	Human lung cancer A549 cell, melanoma cell line B16F10	1, 6, 12 and 30 μg/mL		Block of PAK1 and melanogenesis by down-regulation of intracellular tyrosinase activity	Japan	[144]
EE	Colon Tumorigenesis in male F344 rats	1% EE or WE, basal diet, 25 weeks	In vivo	Tumorigenesis decrease	Brazil	[145]
EE	Gastric cancer in Male Wistar rats	Enriched feed, 36 weeks	In vivo	Significantly decrease of IHC β-catenin positive tumors	Iran	[146]
EE	Bladder cancer in female Wistar rats	150 mg/Kg/day, intragastric, 40 weeks	In vivo	Chemo-preventive effects	Brazil	[147, 148]
EE	Dysplasia of tongue in male Wistar rats	100–400 mg/Kg, intraperitoneall, 20 weeks	In vivo	Tumor decrese	Iran	[149]
EE	Bladder Carcinogenesis in male F344 rats	0.125 to 1%, dietary administration, 32 weeks	In vivo	Enhances of BBN-initiated urinary bladder carcinogenesis via non-mutagenic mechanisms	Brazil	[150]
EE	Male Swiss albino mice	50 mg/Kg, gastric incubation, 7 days	In vivo	Tumor growth and proliferation inhibition; Increase of macrophages tumoricidal activity	Brazil; Zagreb, Croatia	[151]
EE	Male and female CBA inbred mice	50 or 150 mg/Kg, gauge administration, 3 days	In vivo	Suppression of tumor growth and metastases; Antimetastatic activity mediated by immunomodulatory effects	Brazil, Zagreb, Croatia	[152, 153]
EE	Female athymic Fox N1-nu/nu mice	500 or 1000 mg/Kg/day, p.o., 3 weeks	In vivo	Mitotic cell and Ki-67 expression decrease and increase in endoreduplications and p53 expression	Mosul, Iraq	[129]
EE	C57BL/6 male mice	200 mg/Kg, 14 days	In vivo	Transcription of stress stimulated Th1 cytokine (IL-2 and IFN-γ) and Th2 cytokine IL-10	Brazil	[154, 155]
EE	Female ICR mice	2.5 and 5%, oral administration, 6 days	In vivo	Suppressive effects on tumor-induced angiogenesis	Brazil	[156]
EE	OIRM in C57BL/6 mice	300 mg/Kg/day, subcutaneous administration, 5 days	In vivo	Suppression of retinal neovascularization	Brazil	[157]
EE	Female Swiss mice	500 mg/Kg/day, orally, 14 days	In vivo	Progressively increase of blood vessel number	Brazil	[158]
EE	Bladder cancer in female Wistar rats	150 mg/Kg/day, 40 weeks	In vivo	Decrease of microvascular density	Brazil	[159]

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