Table 2.

Summary of polyphenol and chemotherapeutic combination therapies in in vivo preclinical investigations.

Polyphenol	Cancer	Chemotherapy Drug	Dosage	Assay	Molecular Effect	Conclusion	Reference
Apigenin	Liver cancer	Paclitaxel	1 mg/kg/day apigenin + 3.5 mg/kg/day paclitaxel	Balb/c nude mice	Suppressing the intratumoral expression of HIF-1a via inhibiting the AKT/p-AKT pathway and the expression of HSP90 simultaneously	Apigenin reduced hypoxia-induced paclitaxel resistance in hypoxic tumors	[119]
	Lung cancer	Navitoclax	25 mg/kg apigenin + 100 mg/kg ABT-263	BALB/c nude mice	Upregulated the expression of Noxa by targeting the AKT–FoxO3a pathway and inhibited ERK	Apigenin synergized with ABT-263 by suppressing the growth and proliferation of tumor cells in vitro and in vivo	[120]
EGCG	Lung cancer	Cisplatin	EGCG (1.5 mg/mouse/day IP) for 5 days and cisplatin (2 or 4 mg/kg IP) on day 5; EGCG (1.5 mg/mouse/day) and single-dose cisplatin (2 mg/mouse) on day 0 or 5	A549 cell xenograft bearing BALB/c nude mice	Increased cisplatin concentration in tumor tissue and tumor growth delay due to EGCG-induced vascular normalization	EGCG synergistically potentiated cisplatin antitumor efficacy especially when cisplatin was applied during the vascular normalization window	[121]
	Liver cancer	Sorafenib	100 mg/kg EGCG + 10 mg/kg sorafenib	Diethyl nitrosamine-induced hepatocellular carcinoma in Wistar albino rats	Histopathological observations revealed a satisfying decline in tissue degeneration and hyperchromatism. Significantly lower alpha-fetoprotein and liver enzyme levels were detected, as well as a greater antioxidant capacity	EGCG and sorafenib combination had a comparable effect as that of standard-dose sorafenib. The combination resulted in enhanced chemoprotection and is considered effective against hepatocellular carcinoma	[122]
Resveratrol	Colorectal cancer	5-FU	10 mg/kg b.w. resveratrol p.o./day + 12.5 mg/kg b.w. 5-FU i.p. injected on days 1, 3, and 5; repeated every 4 weeks for 4 months	Methyl nitrosourea-induced colon cancer in male albino rats	Decrease of NF-κB and reduction of COX-2, induced p53 gene expression	Resveratrol biochemically modulated and enhanced the therapeutic effects of 5-FU	[123]
	Lung cancer	Gemcitabine	25 mg/kg gemcitabine i.p. 2×/week + 1 µmol/kg resveratrol 5×/week	HCC827 xenografts in nude mice	Downregulation of mRNA and protein levels of ENG, activation of ERK signaling pathway	Resveratrol promoted tumor microvessel growth, increased blood perfusion and drug delivery into tumor that resulted in enhanced anticancer effect of gemcitabine	[124]
Quercetin	Breast cancer	Cisplatin	30 mg/kg quercetin + 7 mg/kg cisplatin	Breast tumor-bearing mouse model	Inhibited tumor growth and reduced renal toxicity	Synergistic effect; inhibited renal toxicity induced by cisplatin	[125]
	Liver cancer	Sorafenib	7.5 mg/kg/day sorafenib, 2 h later 50 mg/kg/day quercetin	Chemically induced HCC rat model	Suppressed proliferation, enhanced apoptosis and necrosis	Synergistically increased anticancer effect and increased liver recovery	[126]
Curcumin	Lung cancer	Gefitinib	1 g/kg CUR + 100 mg/kg gefitinib	BALBL/c mice	Inhibition of Sp1/EGFR activity to induce autophagy-mediated apoptosis	Reduction in tumor volume. Elevated the sensitivity to gefitinib in NSCLC patients with mutated EGFR	[127]
	Liver cancer	5-FU	56.65 mg/kg curcumin + 10 mg/kg 5-FU	BALB/c nude mice	Decreased expression of NF-κB protein in the nucleus. Increased expression of NF-κB protein in the cytoplasm. Downregulation of COX-2 expression	Synergistic effects and in vivo tumor growth inhibition	[128]