Table 1.

In vitro studies on the synergistic effects of selected polyphenols in combination with chemotherapeutics and other natural compounds in CRC treatment.

Polyphenol	Combination with	Cell Line Model	Main Outcome	Reference
Curcumin	5-FU	HCT116 and HCT116 + ch3 parental cells; 5FU-resistant clones (HCT116R, HCT116 + ch3R)	↓ Colonosphere formation, cell growth ↑ Apoptosis ↓ ALDH1, CD44, CD133	[64]
	5-FU	HCT116 and SW480 parental cells; 5FU-resistant clones (HCT116-5FUR, SW480-5FUR)	↓ EMT, proliferation ↑ Apoptosis, cell cycle arrest ↑ miR-200b, miR-200c, miR-141, miR-429 and miR-101 ↓ EZH2, BMI1, SUZ12 and Ring1B	[26]
	5-FU	5FU-resistant HCT8 cells	↑ Apoptosis, cell cycle arrest (G0/G1) ↓ HSP27, P-gp	[74]
	5-FU	5FU-resistant HCT116 cells	↓ EMT, proliferation, WNT signaling ↑ Apoptosis, cell cycle arrest (G0/G1) ↓ NKD2, TET1	[73]
	Cisplatin	HCT8 parental cells and HCT8/DDP-resistant cells	↓ Cell viability ↑ Apoptosis ↓LncRNA KCNQ1OT1, Bcl2 ↑ miR-497	[87]
	Cisplatin	HT-29 and LoVo cells; cisplatin-resistant HT-29 cells	↓ Proliferation ↑ Apoptosis ↑ miR-137 ↓ Glutaminase	[63]
	Dasatinib	HCT116 and HT-29 parental cells; resistant cells (CR-HCT116 and CR-HT-29)	↓ Cell growth, colonosphere size. and extracellular matrix invasion ↓CD133, CD44, CD166, and ALDH1	[65]
	Dasatinib	HCT-116 p53w), HT-29, HCT-116 p53−/−, and SW-620 cells	↓ Cell growth, colony formation and metastasis3 ↓ BcLxL, COX-2, EGFRs, IGF-1R c-Src signaling, p-Akt, p-Erk and NF-κB	[107]
	Doxorubicin	Doxorubicin-resistant HT-29 cells	↓ Colony formation, proliferation ↓ COX-2, LDH, MDR1, P-gp	[93]
	FOLFOX	Chemo-surviving HCT-116 and HT-29 cells	↓ Cell viability ↓ AKT, COX-2, cyclin-D1, EGFR, HER-2, IGF-1R	[95]
	Irinotecan (CPT-11)	LoVo parental cells and LoVo/CPT-11-resistant cells	↓ Cell growth and tumor sphere formation ↓ CD24, CD44, CD133 and EpCAM ↑ Apoptosis	[89]
	Irinotecan (CPT-11)	LoVo parental cells and LoVo/CPT-11R-resistant cells	↓ Proliferation ↑ Apoptosis ↑ E-cadherin ↓ Vimentin and N-cadherin	[90]
	Irinotecan	LoVo and HT-29 cells	↓ Cell viability ↑ Apoptosis, cell cycle arrest, ER stress, ROS generation	[88]
	Oxaliplatin	Oxaliplatin-resistant HCT116 p53wt and p53−/− cells	↓ Proliferative capacity ↓ ALDH1, Notch1, survivin ↑ p21, p53	[77]
	Oxaliplatin	HT29, LoVo, and DLD1 parental cells. Oxaliplatin-resistant sublines HTOXAR3, LoVOXAR3 and DLDOXAR3,	↓ Proliferation and colony formation ↓ CXCL1, CXCL8, and CXCL2 ↓ Akt/NF-κB pathway	[82]
	Oxaliplatin	HCT116 parental cells and HCT116/OXA	↓ Cell growth and EMT ↓ Bcl-2, p-p65 p-Smad2, p-Smad3, and N-cadherin ↑ Cleaved caspase-3 and E-cadherin	[84]
Curcuminoids	5-FU	HT-29 and SW480 cells	↓ Cell growth ↑ ROS production ↓ MDR1, miR-27a, Sp1, Sp3, and Sp4 ↑ ZBTB10	[75]
Resveratrol	5-FU	HCT-116 parental cells and 5-FU-resistant HCT-116R	↓ Cell viability, colony formation, invasion, migration, and proliferation ↓ ALDH1, β1-integrin CD44, CD133, HIF-1α, NF-kB, and VEGF	[130]
	5-FU	HCT116 and SW480 parental cells; 5-FU-chemoresistant derived clones (HCT116R and SW480R)	↓ EMT and proliferation ↑ Claudin-2, desmosomes, and E-cadherin ↓ Caspase-3, IκBα kinase, IκBα, MMP-9, NF-κB, vimentin, and slug	[25]
	5-FU	DLD-1, SW480 and COLO201 parental cells; 5-FU-resistant (DLD-1/5FU)	↓ Cell viability and proliferation ↑ Apoptosis ↑ miR-34a ↓ MAPK/Erk1/2 signaling and PI3K/Akt signaling ↓ E2F3/Sirt1	[42]
	5-FU	DLD-1 and HCT116 cells	↓ Cell viability and EMT ↑ Apoptosis, cell cycle arrest ↓ Akt, NF-κB, p-NFκB, p-STAT3, and STAT3	[117]
	5-FU	HCT116 parental cells; 5-FU-chemoresistant derived clone (HCT116R)	↓ Stemness, EMT, proliferation and TNF-β induced chemoresistance ↑ Cleaved caspase-3, E-cadherin ↓ ALDH1, CD133, CD44, CXCR4, MMP-9, NF-κB, vimentin and slug	[118]
	5-FU	HT-29 and SW620 cells	↓ Cell viability ↑ Apoptosis, lipid peroxide accumulation, and ROS production ↓ Akt and STAT3	[119]
	Doxorubicin	Caco-2 cells	↓ Cell viability ↑ Apoptosis ↑ Caspase-3, caspase-8, and caspase-6/9 ↓ BCRP, CYP3A4 GST, hPXR, MDR1, and MRP1	[125]
	Doxorubicin	HCT116 and HT-29 cells	↓ Cell viability ↑ Apoptosis, cell cycle arrest ↑ p53 and Bax ↓ Bcl-xL and P-gp	[140]
	Oxaliplatin	HCT116 and HT-29 cells	↓ Cell viability, invasion, migration, and proliferation ↑ Apoptosis ↑ miR-34c ↓ PI3K/Akt	[139]
	Oxaliplatin	Caco-2 cells	↓ Cell viability ↑ Apoptosis, DNA fragmentation, secondary necrosis, and alteration in cytokine profile ↑ Cleaved caspase-3, cleaved PARP, IL-8, IL-10 and TNF-α	[120]
EGCG	5-FU	DLD-1 and HCT116	↓ Cell viability ↑ Apoptosis, DNA damage ↑ Cleaved caspase-3 and PARP, miR-155-5p, and NF-κB ↓ Bcl-2, GRP78, MDR1	[157]
	5-FU	HCT116 and SW480 parental cells; 5FU-resistant clones (5FUR-HCT116 and 5FUR-SW480)	↓ Cell viability, proliferation, and spheroid-forming capacity. ↑ Apoptosis, cell cycle arrest, ↑ miR-34a, miR-145, and miR-200c ↓ Bmi1, Ezh2, Notch1 and Suz12.	[156]
	Cisplatin	DLD-1 and HT-29 cells	↓ Proliferation ↑ Apoptosis and autophagy ↑ Acidic vesicular organelles, autophagosome and LC3-II protein.	[164]
	Irinotecan	HCT116 and RKO cells	↓ Cell viability, invasion, and migration ↑ Apoptosis, autophagy, cell cycle arrest, and DNA damage ↑ ATM, p-ATM, p-RB and γ-H2AX ↓ CDK4, Cyclin B1 and Cyclin D1 and TOP1	[161]
	Oxaliplatin	DLD-1 and HT-29 cells	↓ Proliferation ↑ Apoptosis and autophagy ↑ Acidic vesicular organelles, autophagosome, and LC3-II protein.	[164]
Quercetin	5-FU	CO115 p53wt, HCT15 p53mt, HCT116 p53wt and HCT116 p53mt cells	↓ Cell viability and proliferation ↑ Apoptosis ↓ Bcl-2 ↑ Cleaved caspase-3/9 and PARP, p53	[173]
	5-FU	HCT116 parental cells and 5-FU-resistant HCT116 cells (HCT116-R)	↓ Cell viability, proliferation, and ROS production ↑ Apoptosis ↓ CAT, GPx, GR, HO-1, Nrf2, SOD-1, and p-IKBα.	[178]
	5-FU	HT-29 cells	↓ Cell viability ↑ Apoptosis ↓ Akt, Bcl-2, mTOR, VEGF ↑ Bax, p38 MAPK, p53, and PTEN	[187]
	5-FU	Resistin-treated DLD-1 and HCT116 cells	↓ Cell viability ↑ Apoptosis ↓ NLRP3 and p-ERK	[189]
	Alantolactone	CT26-FL3 cells	↑ Immunogenic cell death	[250]
	Curcumin (co-delivery in shellac nanocapsules)	HT-29 and HCT116 cells	↓ Proliferation ↑ Antioxidant capacity	[246]
	Doxorubicin	HT-29 cells	↓ Cell viability, proliferation, and stemness ↑ Apoptosis and cell cycle arrest	[191]
	Doxorubicin	P-gp-overexpressed SW620/Ad300 cells	↓ D-glutamine and D-glutamate metabolism ↓ Proliferation, ↑ Apoptosis ↓ P-gp and SLC1A5	[190]
	FOLFOX + Trans-pterostilbene + radiotherapy	HT-29 cells	↓ Cell viability ↑ SOD2 ↓ Bcl-2, IκBα, p-IκBα, NF-κB,	[259]
	Oxaliplatin	HCT116 cells	↓ Cell viability, glutathione reductase activity, and intracellular glutathione ↑ ROS production	[188]
	Resveratrol	HT-29 cells	↓ ROS production ↑ Apoptosis and antioxidant capacity ↑ Cleaved caspase-3 and PARP, ZBTB10 ↓ miR-27a, Sp1, Sp3, Sp4, and survivin	[247]
Kaempferol	5-FU	LS174 parental cells and 5-FU-resistant LS174-R cells	↓ Cell viability and ROS production ↑ Apoptosis, cell cycle arrest, ↑ Cleaved caspase-3, caspase-9 and PARP, p-Erk1/2 ↓ DHFR, FPGS, FOXO3a, IL-8, p-Akt, p-NFκB, p-STAT3, p-p38MAPK, VEGF-A, TK, and TS	[230]
	5-FU	HCT-8 or HCT-116	↓ Cell viability and proliferation ↑ Apoptosis ↑ Bax and PTEN ↓ Akt, Bcl-2, PI3K, p-AKT and TS	[229]
	5-FU	HCT-8 parental cells and 5-FU-resistant HCT-8R cells	↓ Cell viability, glycolysis, and proliferation ↑ Apoptosis ↑ miR-326 ↓ hnRNPA1, hnRNPA2, PTBP1 and PKM2	[231]
	Oxaliplatin	Oxaliplatin-sensitive HCT116 (HCT116-OxS) and HT-29 (HT29-OxS) parental cells; Oxaliplatin-resistant HCT116 (HCT116-OxR) and HT-29 (HT29-OxR) cells	↓ Proliferation ↑ Cell cycle arrest ↓ c-Fos protein, RSK1, and RSK2	[233]
Genistein	5-FU	HT-29 cells	↓ Cell viability and ROS production ↑ Apoptosis ↓ COX-2, Glut1 ↑ AMPK, PARP, p21, p53	[243]
	Cisplatin	HT-29 cells	↓ Cell viability ↑ Apoptosis	[244]
Apigenin	5-FU	HCT116 and HT-29 cells	↓ Cell viability and proliferation ↑Apoptosis, cell cycle arrest, Ca2+ accumulation, mitochondrial membrane disruption, and ROS production ↓ TS	[196]
	5-FU (dual-drug-loaded liposomal nanocarrier)	HCT-15 and HT-29 cells	↓ Cell viability, colony formation and proliferation ↑ Apoptosis, angiogenesis, cell cycle arrest mitochondrial membrane destabilization and ROS production ↓ COX-2, HIF-1α and p-mTOR ↑ p-AMPK	[197]
	Chrysin	HCT116 and SW480 cells	↓ Colony formation, invasion, and migration ↑ Apoptosis ↓ p-P38 and p-AKT	[255]
	Cisplatin	Cisplatin-resistant HT-29 cells	↓ Cell viability ↑ Apoptosis and autophagy ↓ Bcl-2, p-mTOR, p-PI3K, and p-AKT ↑ Bax	[200]
	Irinotecan	HT-29 and HRT-18 cells	↑ CD26, DPPIV and eADA	[199]
Luteolin	5-FU	HT-29 cells	↓ Cell viability ↑ Apoptosis ↓ Akt, Bcl-2, mTOR, VEGF ↑ Bax, p38 MAPK, p53, and PTEN	[187]
	Baicalein	LoVo parental cells and doxorubicin-resistant subline (LoVo/Dx)	↓ Cell viability and proliferation ↑ Apoptosis and DNA fragmentation ↓ PCNA ↑ Caspase-3 activity	[260]
	Curcumin	CL-188 and DLD-1 cells	↓ Cell proliferation and migration ↓ Notch1 and TGF-β	[256]
	Oxaliplatin	SW480 cells	↓ Cell viability ↑ Apoptosis and oxaliplatin uptake ↑ PDZK1, PDZK2, and OCTN2	[219]
	Oxaliplatin	HCT116 and SW620 parental cells; oxaliplatin-resistant lines (HCT116-OX and SW620-OX)	↓ Cell viability ↓ Nrf2 and NQO1	[211]
	Oxaliplatin	HCT116 cells (p53+/+ and p53−/−)	↓ Cell viability, colony formation, and cell cycle arrest ↑ Apoptosis ↑ Akt, cleaved PARP, p53, Nrf2/ARE/HO-1 axis.	[212]

↑ Upregulation; ↓ Downregulation.