TABLE 1.

Interaction of propolis extracts with chemotherapeutic drugs and their associated mechanisms.

Chemotherapies	Propolis extracts	Source	Study type	Subjects	Key results	Molecular mechanisms	References
DOX	Ethanolic extract	Algeria	In vitro	Breast cancer cells (MDA-MB-231)	Potentiated antitumor effects	Inducing cell cycle arrest in the S phase	Rouibah et al. (2021)
				Normal cells (MRC-5)	Reduced multidrug resistance	Enhanced caspase-dependent apoptosis
					Reduced cytotoxic effect in normal cells	A significant increase in intracellular DOX content by inhibiting p-gp
	Ethanolic and methanolic extract	Algeria	In vivo	DOX-induced mitochondrial stress in rats	Propolis protected heart and liver tissues from oxidative stress	Mitochondria protection by reducing malondialdehyde, restoring glutathione contents and catalase and superoxide dismutase activities	Badr et al. (2015)
	Ethanolic extract	Australia	In vitro	MCF7 breast adenocarcinoma	Strong synergistic interaction (CI = 0.11) in inhibiting cell proliferation	Upregulated expression of pro-apoptotic protein cyclin-dependent kinase inhibitor 1B (p27), antioxidant PON2, Claspin and catalase, and downregulated expression of anti-apoptotic protein including XIAP, HSP60, and HIF-1α	Alsherbiny et al. (2021)
	Propolis capsules	Australia	In vivo	DOX-induced multi-organ toxicity in rats	Pre-treatment with propolis significantly ameliorated DOX-induced cardiomyopathy, hepatotoxicity, nephritis, and pneumonia	Reduced apoptosis, oxidative stress and pro-inflammatory cytokines	Mohamed et al. (2021)
	Hydroalcoholic extract	Brazil	In vivo	Wistar rats	The co-administration reduced chromosome damage induced by DOX compared to the group treated only with DOX	Free radical scavenging activity by the phenolic compounds in propolis	Tavares et al. (2007)
	Methanolic extracts	Cuba	In vitro	Human colon carcinoma cells (LoVo Dox)	Synergistic antiproliferative and cytotoxic effect	Induced cell cycle arrest	Frión-Herrera et al. (2019)
						Increased level of apoptosis
						Marked ROS production and drastic alteration of ΔΨm
	Ethanolic extract	Chandigarh, India	In vivo	DOX-induced hepatotoxicity in male rats	Administration of animals with propolis prior to DOX led to significantly reduced hepatotoxicity parameters in blood when compared to the doxorubicin-treated group.	Modulation of the oxidative damage related parameters in liver	Singla et al. (2014)
	Propolis extract	Egypt	In vivo	DOX-induced cardiotoxicity and nephrotoxicity in rats	Propolis exhibited protective effects against DOX-induced cardiotoxicity and nephrotoxicity	Propolis attenuated cardiac oxidation and lowered lipid level	Ali et al. (2020)
	Ethanolic extract	Egypt	In vivo	DOX-induced testicular toxicity in rats	Propolis extract ameliorated DOX-induced toxicity in testis without reducing its anti-cancer potential	Restored levels of testosterone, follicle-stimulating hormone (FSH), and luteinizing hormone (LH) in normal and DOX-treated rats; restored testicular activities by regulating 3b-hydroxysteroid dehydrogenase (3b-HSD) and 17b-hydroxysteroid dehydrogenase (17b-HSD); free radicals scavenging and improving antioxidant enzymes in various tissues; reduced inflammatory and apoptotic responses	Rizk et al. (2014)
	Aqueous extract	Egypt	In vivo	N-methyl-N-nitrosourea (MNU) induced adenocarcinoma in rats	The combination protected liver and kidney against the toxicity of DOX	Restored liver enzyme levels including albumin, globulin, ALT, AST, ALP; improved kidney function; improved activities of antioxidant enzymes	Badr et al. (2015)
	Water extract of propolis	NA	In vivo	DOX-induced somatic mutation and recombination in Drosophila melanogaster	The combined treatment led to a reduction in the frequency of recombination compared to the treatment with DOX alone	NA	Valadares et al. (2008)
	Ethanolic extract	NA	In vivo	DOX-induced hepatotoxicity in rats	Improved hepatoprotective effect shown as number of vacuolated hepatocytes with mild congestion in central veins	NA	Omar et al. (2016)
TEM	Ethanolic extract	NA	In vitro	U87MG glioblastoma	The combination therapy significantly reduced cell viability and proliferation	Reduced DNA synthesis, enhanced cell permeability, and significantly reduced NF-κB translocation	Markiewicz-Żukowska et al. (2013)
Irinotecan	Ethanolic/aqueous extracts of propolis	NA	In vivo	Swiss albino mice injected with EAT	The combination with the ethanolic extract of propolis increased the life span of the tumor-bearing mice and decreased proliferation of the EAT compared to using irinotecan alone	NA	Benkovic et al. (2007); Lisičić et al. (2014)
	Ethanolic/aqueous extracts of propolis	NA	In vivo	Swiss albino mice injected with EAT	Combined treatment with aqueous or ethanolic extracts of propolis showed enhanced antitumor activity and prolonged survival in EAT-bearing mice	NA	Lisičić et al. (2014)
	Water-soluble derivative of propolis	NA	In vivo	Swiss albino mice injected with EAT	The combination treatment resulted in substantial inhibitions of the growth of EAT cells; decreased genotoxic and cytotoxic to normal cells induced by irinotecan	Immunomodulatory effect regulating lymphocyte/polymorphonuclear leukocyte ratio	Oršolić et al. (2010)
5-Fu	Aqueous extract	Brazil	In vivo	EAT mouse model	The co-administration significantly increased tumor regression compared with using 5-Fu alone and significantly ameliorated the cytopenia induced by 5-FU	Restored white and red blood cell counts	Suzuki et al. (2002)
	Alcoholic extract	Iran	In vivo	AOM/DSS induced colorectal cancer in BALB-c mice	Propolis increased the anti-cancer of 5-Fu by further inhibiting the onset and progression of colorectal cancer	A greater decrease in Cox-2 and iNOS expression leading to reduced cell survival	Sameni et al. (2021)
MMC	Ethanolic extract	Turkey	In vitro	Human peripheral lymphocyte viability	The co-incubation of either propolis extract and MMC enhanced the cell viability of lymphocyte compared to using MMC alone	NA	Arslan et al. (2021)
	Ethanolic extract	Iraq	In vivo	Albino male mice	Propolis may have the potential to inhibit the genotoxic effects of MMC without compromising the anti-cancer activity of MMC	Immunomodulatory capacity of propolis through a significantly increased total count of leucocytes and mitotic index	Al-Halbosiy (2008)
	Hydroethanolic extract	India	In vivo	Healthy adult male mice	The co-administration protected testis against the toxicity from MMC	Reduced DNA damage, elevated the anti-oxidant activity, restored the testicular testosterone and inhibin B level	Kumari et al. (2017)
	Hydroethanolic extract	NA	In vivo	MMC-induced bone marrow toxicity in Swiss albino mice	Hydroethanolic extract of propolis possessed substantial geno- and cytoprotective properties against MMC	Free radical scavenging activity of propolis	Kumari et al. (2016)
	Aqueous extract	NA	In vivo	EAT mouse model	Significantly increased tumor regression compared to using MMC alone and attenuated cytopenia induced by MMC	Restored white blood cells, red blood cells, and platelet counts	Suzuki et al. (2002)
PDT	Ethanolic extract	Seoul, South Korea	In vitro	Human head and neck cancer cells AMC-NH-4	The combined treatment enhanced the inhibition of tumor cell viability and increased apoptotic level	Upregulated caspase-mediated cell apoptosis	Ahn et al. (2013)
	Ethanolic extract of green propolis	Brazil	In vitro and in vivo	Human epidermoid carcinoma A431 cell and cervical cancer HeLa cell, xenograft mouse model	Synergistic effect (CI < 1) in reducing tumor cell viability in the combination and suppressed inflammatory response	Increased PDT intracellular uptake and accumulation; upregulated Bax/Bcl-xL and caspase-mediated cell apoptotic level; inhibited pIKK-NFκB signaling pathway	Wang et al. (2017)

NA, not available.