Table 1.

Combination of experimental design of natural compounds with other natural products and the outcomes of these studies.

Natural Compounds	Chemical Classification	Combination Therapy	Concentrations Used	Type of Cancer	Experimental Model	Outcomes of the Combination	Intersecting Mechanisms	References
Curcumin	Diarylheptanoid, phenolic compound	Curcumin/Resveratrol	Curcumin 15 mM Resveratrol 15 μM	Breast cancer Salivary cancer	In vitro	Reducing cancer cell viability, increased ER stress and activation of the pro-death UPR protein CHOP	Apoptosis	[49]
		Curcumin/Soy isoflavones	Curcumin 20 mM Isoflavones 10 mg/mL	Prostate adenocarcinoma	In vitro	Reduced the concentration of PSA	Anti-androgen effect	[48]
		Curcumin/Emodin	Curcumin 30 μM Emodin 80 μM	Breast cancer	In vitro	Reduced tumor growth and invasion by inducing the expression of miR-34a	Inhibition of proliferation and invasion of breast cancer cells through upregulation of miR-34a	[55]
		Curcumin/ EGCG	Curcumin 3 mM EGCG 25 μM	Breast cancer	In vitro In vivo	Suppress ERα-breast cancer cell growth	G2/M-phase cell cycle arrest	[54]
		Curcumin/Thmoquinone	Curcumin 24.91 µM TQ 41.16 µM	Breast cancer	In vitro	Showed synergistic effect in reducing tumor cells growth via increasing caspase-3 and decrease PI3K and AKT	Cell proliferation inhibition Apoptosis induction	[56]
		Curcumin/Gemcitabine	Curcumin 10 μmol/L Gemcitabine 50 nmol/L	Pancreatic cancer	In vitro In vivo	Prevent the production, development, invasion, and metastasis of proteins (NF-B, EGFR, VEGF, COX-2, miRNA-22, Bcl-2, Bcl-xL, and others) upregulating Bax and caspases	Inhibition of proliferation, angiogenesis, and invasion	[58]
		Curcumin/Vitamin D	Curcumin 10−5 M 1.25D 10−7 M	Colon cancer	In vitro	Improved anticancer effect by interacting with vitamin D receptors	Activating vitamin D receptor (VDR) inducing the VDR target genes CYP3A4, CYP24, p21 and TRPV6. In the colon, some of these yet-to-be identified genes may play a role in cancer chemoprevention	[59]
		Curcumin/Quercetin	curcumin 3.1 μM and 6.2 μM Quercetin 25 μM and 50 μM	Human malignant melanoma	In vitro	Inhibition of proliferation, modulation of Wnt/β-catenin signaling and apoptotic pathway	Inhibition of cell proliferation through down-regulation of Wnt/β-catenin signaling pathway proteins, DVL2, β-catenin, cyclin D1, Cox2, and Axin2	[60]
		Curcumin/Boswellic acid	curcumin, 10 μmol/L AKBA 30 μmol/L	Colorectal cancer	In vitro In vivo	Induced chemoprevention through modulating miRNAs and their downstream target genes involved in cell-cycle control	Suppression of tumor growth by Induction the upregulation of tumor-suppressive miR-34a and downregulation of miR-27a in colorectal cancer cells	[47]
Resveratrol	Stilbeniod, phenolic compound, and a phytoalexin	Resveratrol/Curcumin	Resveratrol dose level of 5.7 mg/mL three times a week Curcumin dose level of 60 mg/kg of body weight three times a week	Lung cancer	In vivo	Synergistically stimulated p21 and modulated Cox-2 expression	expression of p21 significant decrease in tumor incidence and multiplicity curcumin and resveratrol have been reported to modulate p21 expression by a p53-dependen pathway adequate zinc levels along with phytochemicals resulted in efficient cell cycle arrest by p21 to control rapid cell proliferation	[80]
		Resveratrol/Melatonin	Resveratrol pellets in a concentration of 100 mg/kg Melatonin Drinking water pellets in a concentration of 100 mg/kg	Breast cancer	In vivo	NMU-induced mammary carcinogenesis was not affected by either agent alone, but when they were combined it resulted in a significant decrease in tumor incidence.	reduced tumor incidence by approximately 17% and significantly decreased the quantity of invasive and in-situ carcinomas returned food intake to the level of intact controls (significantly increased food intake) protective effects on NMU-induced rodent breast cancer	[81]
Genistein	Phytoestrogenic isoflavone	Genistein/Capsaicin	genistein 50 μmol/L Capsaicin 50 μmol/L	Breast cancer	In vitro	Synergistic apoptotic and anti-inflammatory effects	Reduced cell viability chromatin condensation and nuclear fragmentation stimulating AMPKα1	[97]
		Genistein/Sulforaphane	Genistein 15 µM Sulforaphane 5 µM	Breast cancer	In vitro	Promoted cell cycle arrest	downregulated KLF4 downregulated HDAC activity especially HDAC2 and HDAC3 downregulated hTERT	[101]
EGCG	Catechin/polyphenol	EGCG/curcumin	EGCG 50 and 100 μM curcumin 50 μM	Prostate cancer	In vitro	Arrested S and G2/M cycles	Arrested both S and G2/M phases of cell cycle Synergic up-regulation of p21 and followed cell growth arrest	[116]
		EGCG/Quercetin	EGCG 100 μM Quercetin 10 and 100 μM	Breast cancer	In vitro	EGCG had improved the anti-metabolic effect of quercetin in ER-negative breast cancers also it had decreased the viability and proliferation of MCF7 cells	Decreased cellular proliferation Inhibit glucose uptake by cells Metabolic antagonists in breast cancer cells, independently of estrogen signaling	[117]
		EGCG/Resveratrol	EGCG 30 μM resveratrol 15 μM	Head and neck cancer	In vivo	Enhanced apoptotic effect and reduced tumor growth	Increased apoptosis	[120]
		EGCG/Sulforaphane	EGCG 20 mM Sulforaphane 10 mM	Ovarian cancer	In vitro	Provoked apoptosis in ovarian resistant cells through human telomerase reverse transcriptase(hTERT) and Bcl-2 down regulation	arrest cells in both G2/M and S phase increases apoptosis in paclitaxel-resistant SKOV3TR-ip2 cells by down-regulating of hTERT and Bcl-2 and promote DNA damage response reducing the expression of hTERT	[119]
Allicin	Thiosulfinate	Allicin/ Thymoquinone	PC3 cells Allicin 24 g/mL Thymoquinone 500 g/mL CaCo2 cell Allicin 12 g/mL Thymoquinone 500 g/mL	Prostate and colon cancer	In vitro	Modulated antioxidant parameters	Increase of catalase activity in both PC3 cells and Caco2 cell	[141]
		Allicin/Methylsulfonylmethane	They used the IC50 MSM/allicin For CD44− 55.71 ± 8.47 mg/mL MSM/allicin For CD44+ 68.83 ± 9.78 mg/mL	Breast cancer	In vitro	Increased expression of caspase-3 mRNA expression	Enhanced more caspase-3 mRNA expression than allicin alone in both CD44± cells. Modulating the expression of the key apoptotic factors.	[143]
Thymoquinone	Monoterpenoid	Thymoquinone/Royal jelly	Thymoquinone 15 µmol/L Royal jelly 5 µg/mL	Breast cancer	In vitro	Enhanced anticancer activity	cell viability inhibition and PreG1 increase	[172]
		Thymoquinone/Quercetin	Thymoquinone 5 μM Quercetin 22.49 and 25.9 μM	Non-small cell lung cancer	In vitro	Induced apoptosis by modulating Bax/Bcl2 cascade	reduce the expression of antiapoptotic protein Bcl2 and induce proapoptotic Bax	[174]
		Thymoquinone/ferulic acid	Thymoquinone 50 and 100 µM ferulic acid 450 µM	Breast adenocarcinoma	In vitro	Synergic growth inhibition	decreased cell proliferation	[173]
		Thymoquinone/Melatonin	Thymoquinone 10 mg/kg/day Melatonin 1 mg/kg twice daily	Breast cancer	In vitro In vivo	Synergic antitumor effect by reducing tumor size with a 60% cure	induction of apoptosis, angiogenesis inhibition, and activation of T helper 1 anticancer immune response	[171]
		Thymoquinone/Resveratrol	TQ 46.03 μM Resveratrol 64.54 μM	Hepatocellular carcinoma	In vitro	Significant cell inhibition and increased caspase-3	cell inhibition and increase in caspase-3 indicating cell apoptosis raised reactive oxygen species leading to decrease of glutathione	[162]
Piperine	Alkaloids	Piperine/Thymoquinone	Piperine 425 μM Thymoquinone 80 μM	Breast cancer	In vivo	Inhibition of angiogenesis, induction of apoptosis, and shift toward T helper1 immune response	decrease VEGF expression and increased serum INF-γ levels angiogenesis inhibition, apoptosis induction, and shifting the immune response toward T helper1 response.	[181]
Emodin	Anthraquinonoe/phenolic compound	Emodin/berberine	Emodin 5–20 μM berberine 5–30 μM	Breast cancer	In vitro	Synergic inhibition of SIK3/mTOR pathway and induction of apoptosis	Attenuated aerobic glycolysis and cell growth as well as induce cell death by suppressing the SIK3/mTOR/Akt signaling pathway	[220]
Parthenolide	Sesquiterpene/germacranolide class	Parthenolide/ginsenoside compound k	parthenolide 7.5 mg/kg ginsenoside compound k 37.5 mg/kg	Lung cancer	In vitro In vivo	Increased tumor targeting	induce mitochondria-mediated lung cancer apoptosis	[233]
		Parthenolide/betulinic acid/honokiol/ginsenoside Rh2	Parthenolide 20.5 mg/kg, betulinic acid 20.3 mg/kg Honokiol 20.7 mg/kg ginsenoside Rh2 20 mg/kg	Lung cancer	In vitro In vivo	Displayed a synergistic activity in liposome systems for lung cancer treatment	cocktail liposome systems may provide a more efficient and safer treatment for lung cancer.	[234]
Luteolin	Digitoflavone/flavonoid	Luteolin/Baicalein	Luteolin 2.5, 5, 12.5, 25, 50, 80 and 100 mM Baicalein 2.5, 5, 12.5, 25, 50, 80 and 100 mM	Colorectal adenocarcinoma	In vitro	Synergic growth inhibition	inhibit cancer cells proliferation	[255]
			Luteolin 10 or 20 μM Quercetin 10, 20, and 40 μM	Cervical cancer	In vitro	Reduction in ubiquitin E2S expression led eventually to metastatic inhibition of cervical cancer	inhibited UBE2S expression	[247]
		Luteolin/Hesperidin	Hesperidin 100 μg/mL Luteolin 100 μg/mL	Breast cancer	In vitro	Induced cell cycle arrest by mediating apoptosis and downregulation the miR-21 expression	inhibition of cell proliferation, migration, and invasion reduced cell viability accumulation of apoptotic cells into the G0/G1 and sub-G1 cell cycle phases induced apoptosis through the intrinsic and extrinsic pathways, down-regulated anti-apoptotic, Bcl-2, and upregulated pro-apoptotic, Bax downregulated the expression of miR-21 and upregulated that of miR-16 and -34a in MCF-7	[249]
		Luteolin/Silibinin	Luteolin 20 µM Silibinin 50 µM	Glioblastoma	In vitro	Synergic inhibition of cell proliferation, migration, and invasion	inhibition of cell migration block angiogenesis block survival pathways leading to induction of apoptosis.	[247]
Quercetin	Flavonol/flavonoid	Quercetin/Curcumin	Quercetin 20 µM Curcumin 10 µM	Breast cancer	In vitro	Altered the BRCA1 deficiency and therefore augment the activity of anti-cancer drugs	synergistic action was observed in modulating the BRCA1 level and in inhibiting the cell survival and migration of TNBC cell lines	[258]
			Quercetin 11.39, 0.419 µM, Curcumin 2.85, 53.89 µM	Myeloid leukemia	In vitro	Enhanced apoptotic effect increasing ROS production	act indirectly on inhibition of STAT3 in a number of leukaemia cell lines (HL-60, U-937 and K562)	[259]
		Quercetin/Resveratrol	Quercetin 10 µM Resveratrol 10 µM	Oral cancer	In vitro	Cell growth inhibition, stimulation of apoptosis also it had been noticed to downregulate Histone deacetylase (HDAC)1, HDAC3, and HDAC8	Cell Growth Inhibition, DNA Damage, Cell Cycle Arrest, and Apoptosis in Oral Cancer Cells	[260]
			Quercetin 2 μg/mL Resveratrol 50 μg/mL	Skin cancer	In vivo Ex vivo	Synergistic effect over the use of single drugs	dual drug-loaded nanostructured lipid carrier (NLC) gel of quercetin and resveratrol enhanced their disposition in dermal and epidermal layers	[261]
		Quercetin/Thymoquinone	Quercetin 22.49 µM TQ 22.49 µM	Non-small lung cancer	In vitro	Downregulated BcL2, and activated BAX protein	reduce the expression of antiapoptotic protein Bcl2 and induce proapoptotic Bax, suggestive of sensitizing NSCLS cells toward apoptosis.	[174]
		Quercetin/Luteolin	Luteolin 10 or 20 μM Quercetin 10, 20, and 40 μM	Cervical cancer	In vitro	Lowered the ubiquitin E2S ligase (UBE2S) expression	inhibited UBE2S expression	[248]
Anthocyanins	Flavylium/flavonoid	Anthocyanins/luteolin	Anthocyanins Cyanidin-3-O-glucoside chloride 35 μmol/L luteolin 10 μmol/L	Breast cancer Colon cancer	In vitro	Increased apoptosis and inhibited proliferation	inhibited proliferation and increased apoptosis	[287]