Table 2.

Cellular and molecular mechanism of action of the combination treatment in preclinical studies

Therapeutic agent	Animal model or cell line	Cellular and molecular mechanism of action of the combination treatment	Ref.
Radiation	MCF-7 and T47D human breast cancer cells	Increases the percentage of cells in sub-G1 phase	Velho-Pereira et al[121]
	MCF-7 and MDA-MB-231 human breast cancer cells	Restores the expression levels of TGF-β and its downstream molecules NFkB, Smad2, Snail and Twist, adhesion molecules E-cadherin and cytokeratin 19, mesenchymal markers integrin αV, MMP-9, and MMP-2	Rajput et al[122]
	B16-F10 melanoma cells	Inhibits the phosphorylation of JAK2 and STAT3. Increases the expression of caspase 3 and Bax. Reduce the expression of Bcl-2 and survivin and the level of VEGF-A, MCP-1, TGF-β1, RANTES and IL-1β. Induces DNA damage	Hatiboglu et al[123]
microRNA-34a	BT-549 metastatic breast cancer cells	Targets and downregulates TWIST1 and ZEB1	Imani et al[126]
Akt-siRNA	Akt-overexpressing MCF-7 and T47D. Tamoxifen resistant MCF-7 and T47D breast cancer cells. BALB/c mice injected with MCF-7/TAM cells	Reduces Akt expression and MDM-2 activation. Activates p53, increases the level of Bax and Bim and decreases the level of Bcl-2 and Ki67	Rajput et al[127]
Vitamin D3	Azoxymethane-induced colorectal tumors in Wistar rats	Reduces the level of Wnt, β-catenin, NFkB, COX-2, iNOS, VEGF and HSP-90 and increases that of DKK-1, CDNK-1A, TGF-β1, TGF-β/RII and Smad4	Mohamed et al[131]
Melatonin	EMT6/P mouse breast cancer cells. Balb/C mice transplanted with EMT6/P cells	Reduces the expression of VEGF and the serum level of AST and ALT. Increases the serum level of IFN-α and decreases that of IL-4	Odeh et al[134]
Artemisinin	CCRF-CEM and multidrug-resistant CEM/ADR5000 human leukemia cells. Healthy human foreskin fibroblasts		Fröhlich et al[136]
Artesunic acid	HCT116, HT29, Caco-2, DLD-1 colon cancer cells. HCEC nonmalignant colon epithelial cells	Induces ROS generation, DNA damage, PARP and caspase 9 cleavage. Increases the level of ɣ-H2AX	Fröhlich et al[137]
Diosgenin	A431 and Hep2 human squamous cell carcinoma. Swiss albino mice injected with sarcoma 180 cells	Induces DNA fragmentation and cytoskeletal changes. Decreases the expression of CD31 and Ki67	Das et al[138]
Emodin	MCF-7, MDA-MB-231, MDA-MB-468 and T47D human breast cancer cells. CAM inoculated with MCF-7 cells	Increases the percentage of cells in sub-G1 phase. Increases ROS generation, cytochrome c release, expression levels of p53, Bax and cleaved caspase 3. Reduces Bcl-2, pFAK and integrinβ1 expression level. Induces nuclear fragmentation, shrinkage, apoptotic body formation, chromatin condensation and membrane blebbing	Bhattacharjee et al[140]
Ferulic acid	MDA-MB-231 human breast cancer cells		Al-Mutairi et al[143]
Genistein	CALC-62 and ACC448 human thyroid cells derived from anaplastic carcinoma CGTH-W1, ACC360 derived from follicular carcinoma	Reduces the expression level of human telomerase reverse transcriptase, VEGF-A and NFkB. Increases the expression level of PTEN and p21 and activates caspase 3	Ozturk et al[145]
Indirubin-3-monoxime	A549 human lung cancer cells. HFL-1 human fetal lung fibroblast. CD1-nude mice injected with A549 cells	Increases the percentage of cells in Sub-G0 phase. Reduces Bcl-2/Bax ratio, TNF-α release and p-Akt (s473), p-mTOR, NFkB/p65, caspase3 and p53 expression level	Dera et al[147]
Piperine	EMT6/P mouse mammary cancer cells. Balb/C female mice injected with EMT6/P cancer cells	Reduces VEGF expression. Increases IFN-γ and IL-2 level and caspase 3 activity	Talib et al[149]
	HepG2 human hepatocellular cancer cells	Increase ROS generation and decreases GSH and NADPH level	Das et al[151]
Resveratrol	HepG2 human hepatocellular cancer cells	Increases caspase 3 activity. Decreases GSH and MDA level	Ismail et al[153]
	EMT6/p mouse epithelial breast cancer cells. MCF-7 and T47D human epithelial breast cancer cells kidney epithelial cells. Balb/C mice injected with EMT6/p cancer cells	Induces DNA fragmentation and increases IFN-γ and IL-4 level. Reduces VEGF expression	Alobaedi et al[154]
Selenium	MG-63 human osteosarcoma cell line	Increases cellular damage, and decreases the level of alkaline phosphatase and GSH	Barron et al[156]

PTEN: Phosphatase and tensin homolog; ROS: Reactive oxygen species; Bax: Bcl-2-associated X protein; GSH: Glutathione; MMP: Matrix metalloproteinases; ɣ-H2AX: Gamma-histone 2AX; JAK2: Janus kinase 2; STAT3: Signal transducer and activator of transcription 3; NFkB: Nuclear factor kappa B; COX-2: Cyclooxygenase 2; iNOS: Inducible nitric oxide synthase; VEGF: Vascular endothelial growth factor; DKK-1: Dickkopf-related protein-1; CDNK-1A: Cyclin-dependent kinase inhibitor 1A; TGF-β1: Transforming growth factor beta 1; TGF-βRII: Transforming growth factor beta receptor II; GSH: Glutathione; mTOR: Mammalian target of rapamycin; AST: Aspartate transaminase; ALT: Alanine transaminase; MDA: Malondialdehyde; IL: Interleukin; INF: Interferon; TNF-α: Tumor necrosis factor alpha; MCP-1: Monocyte chemoattractant protein-1; RANTES: Regulated on activation normal T cell expressed sequence; TWIST1: Twist-related protein 1; ZEB1: Zinc finger E-box binding homeobox 1; MDM-2: Mouse double minute 2; NADPH: Nicotinamide-adenine dinucleotide phosphate; CAM: Chorioallantoic membrane.