Table 1.

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

Polyphenol	Cancer	Chemotherapy Drug	Dosage	Assay	Molecular Effect	Conclusion	Reference
Curcumin	Lung cancer	Cisplatin	2–32 µM curcumin + 0.5–8 µg/mL cisplatin.	A549, H1299, NCI-H460 cell lines	Upregulating the levels of CTR1 and Sp1 to increase more Pt2+ uptake.	Enhancing sensitivity and antitumor effects of CIS in NSCLC	[108]
	Colorectal cancer	Oxaliplatin	HCT116 and SW480 cells 0–8 µM curcumin + 0.5–32 µM oxaliplatin; HCT116/oxaliplatin cells 4 µM curcumin + 8 µM oxaliplatin	HCT116, SW480, HCT116/Oxaliplatin drug-resistant cell lines	Inhibition of TGF-β/Smad2/Smad3 signaling	Inhibition of cell proliferation and reduced tumor weight and volume	[109]
	Breast cancer	Doxorubicin	25 µM curcumin + 5 µM doxorubicin	MCF-7/doxorubicin drug-resistant cell line	Reduced Aurora-A expression. Triggered p53 stabilization. Growth arrest and apoptosis induction	Reversed doxorubicin insensitivity and increased sensitivity in doxorubicin-resistant MCF-7 and MCF-7 cell lines	[110]
Quercetin	Liver cancer	Doxorubicin; 5-fluorouracil (5-FU)	40–160 µM quercetin + 0.2–125 µg/mL doxorubicin/5-FU	BEL-7402 and BEL-7402/5-FU drug-resistant cell lines	Inhibition of FZD7/β-catenin pathway and ABCB1, ABCC1, and ABCC2 efflux pump	Enhanced doxorubicin and 5-FU sensitivity	[111]
	Colorectal cancer	Doxorubicin	33 µM quercetin + 0.5 µM doxorubicin	SW620/ doxorubicin drug-resistant cell line and SW620/Ad300 cell line	Reversed P-gp-mediated drug resistance, increased intracellular doxorubicin accumulation; modulated glutamine metabolism in doxorubicin-resistant cells by inhibition of SLC1A5	Reversed MDR, enhanced sensitivity to doxorubicin	[112]
Resveratrol	Lung cancer	Gemcitabine	10 µM RES + 1 µM gemcitabine	HCC827 cell lines and HCC827	Downregulation of mRNA and protein levels of ENG, activation of ERK signaling pathway	RES promoted tumor microvessel growth, increased blood perfusion and drug delivery into tumor that resulted in enhanced anticancer effect of GEM	[113]
	Gastric cancer	Cisplatin	20 μM RES + 1 μg/mL cisplatin	AGS cell line	Upregulation of Bax and the cleaved form of PARP, downregulation of Bcl-2, increased PERK, p-eIF2α, and CHOP protein levels. Activation of PERK/eIF2α/ATF4/CHOP signaling pathway, induction of G2/M cell cycle arrest	Synergistically inhibited cell growth of cancer cell lines	[114]
EGCG	Breast cancer	Arsenic trioxide and/or irradiation	10–100 µM EGCG + 2 Gy radiation; 10–100 µM EGCG and 4 µM arsenic trioxide. 10–100 µM EGCG, 4 µM arsenic trioxide and 2 Gy radiation.	MCF-7 cell lines	Bax upregulation and Bcl-2 downregulation	Combination of EGCG and Arsenic trioxide with or without radiation showed synergistic effects in breast cancer treatment visible in the rise of cell death	[115]
	Lung cancer	Doxorubicin	0.5 μM EGCG + 0–100 μM doxorubicin	Nonresponsive A549 cell line	Decreased drug efflux, MDR signaling, and invasiveness. Increased drug internalization, cell cycle arrest, stress induced damage, and cell death	EGCG reversed the compromised functionality of doxorubicin in a nonresponsive A549 cell line and improved its oxidative damage-mediated antitumor effect by modulating redox signaling	[116]
Apigenin	Colorectal cancer	5-FU	20 µM apigenin + 20 µM 5-FU	HCT116 and HT29 cell lines	Inhibited the upregulation of TS induced by 5-FU. Increased reactive oxygen species production, intracellular and intramitochondrial Ca2+ concentrations, and mitochondrial membrane potential	Apigenin enhanced the efficacy of 5-FU by potentiating HCT116 cell apoptosis and enhancing cell cycle disruption. Acquired resistance to 5-FU was reduced	[117]
	Breast cancer	Cisplatin	5–100 μg/mL apigenin + 5–100 μg/mL cisplatin	MDA-MB-231 and HCC1806 cell lines	Inhibition of telomerase activity. Down-regulation of hTERT, Hsp90, and p23 at transcriptional and translational levels	Apigenin and cisplatin synergistically inhibited telomerase activities by reducing the catalytic subunit of the enzyme	[118]