Table 3.

Table summarizing the combination therapy in the past five years of resveratrol with chemotherapy in the preclinical studies in vitro (cell lines) and in vivo (rodents).

Cancer Type	Chemotherapy	Dosage	Assay Type	Molecular Effect	Study Conclusion	Ref.
Lung cancer	GEM	In vitro: 10 µM RES + 1 µM GEM. In vivo: 25 mg/kg GEM i.p. 2×/week + 1 µmol/kg RES 5×/week	HCC827 cell lines and HCC827 xenografts in nude mice	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.	[157]
Colorectal cancer	5-FU	10 mg/kg b.w. RES 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.	RES biochemically modulated and enhanced the therapeutic effects of 5-FU.	[169]
		0–200 µM RES + 10 µM 5-FU	DLD1 and HCT116 cell lines	Abolished CD44 expression, inhibition of STAT3 and Akt signaling pathways, decreased binding of STAT3 to the hTERT promoter, subsequently reduced telomerase activity.	RES enhanced the antitelomeric and pro-apoptotic potential of 5-FU in CRC, and led to re-sensitization to chemotherapy.	[170]
		5 μM RES + 1 nM 5-FU	HCT116 and HCT116R/5-FU drug-resistant cell lines	Suppressed expression of NF-κB, MMP-9 and CXCR4, induced caspase-3 cleavage, suppressed vimentin, transcription factor slug and induction of E-cadherin.	RES chemosensitizes CRC cells to 5-FU in TNF-β-induced inflammatory tumor microenvironment.	[171]
Liver cancer	CIS	12.5 μg/mL RES + 0.625 μg/mL CIS, 25 µg/mL RES + 1.25 µ/mL CIS	C3A and SMCC7721 cell lines	Reduced glutamine transporter ASCT2 expression and glutamine uptake, affected expression of cytochrome c, caspase-9 and activated caspase-3.	Synergistic effects and enhanced CIS toxicity in human hepatoma cell lines.	[158]
	SOR	In vitro: 80 μM RES + 2.5, 5, 10 μM SOR. In vivo: RES (20 mg/kg, i.p.) + SOR (25 mg/kg, p.o.) 2×/week for 3 weeks.	HepG2, Huh7 HCC cell lines and BALB/c nude mice	Accumulation of cells in S phase and decrease of G0/G1 phase, decreased levels of CDK2 and CDC25A and increased level of cyclin A, increased levels of cleaved caspase-3, caspase-8, and caspase-9 proteins, decreased expression of PKA, p-AMPK, and eEF2K.	Synergistic effects in vitro and in vivo.	[159]
		40, 80 μM RES + 0.25–10 μM SOR	Hep3b and HepG2 cell lines	-	RES potentiated the lethality of SOR.	[104]
Gastric cancer	CIS	20 μM RES + 1 μg/mL CIS	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.	[151]
Breast Cancer	CIS	12.5, 25, 50 μM RES + 4 μM CIS	MDA-MB-231cell lines and female BALB/c mice MDA-MB-231 xenografts	The expressions of P-AKT, P-PI3K, Smad2, Smad3, P-JNK, and P-ERK induced by TGF-β1 were reversed after RES and CIS co-treatment.	Synergistic effect on the inhibition of breast cancer cell viability, migration, and invasion in vitro; enhanced anti-tumor effect and reduced side effect of CIS in vivo.	[160]
		57.5, 72 μM RES + 18.5, 23 μM CIS	MDA-MB-231 cell line	Activation of the caspase-9 and caspase-3 enzymes, higher mitochondrial membrane depolarization.	Co-treatment induced a higher rate of apoptosis.	[161]
		0–250 μM RES + 2–50 μM CIS	MCF-7, MCF-7R, T47-D and MDA-MB-231 cell lines	Enhanced antiproliferative effect, reduction of the HR initiation complex mRNA components in MCF-7 and MCF-7R cells.	Co-treatment lowered the concentrations of CIS needed for the equivalent effect compared with CIS alone.	[162]
	DOX	30 µM RES + 100 nM DOX	MCF7 cell line	-	RES potentiated long-term toxicity of DOX, probably due to the long-term increase of apoptosis and senescence in MCF-7 cells.	[163]
		50 μmol/L RES + 4 μg/mL DOX	MCF-7 and MCF-7/ADR drug-resistant cell lines	RES reversed DOX induced upregulation of vimentin and N-cadherin and β-catenin, upregulated SIRT1 expression, reversed EMT and inhibited cell migration in MCF7/ADR cells.	RES reversed DOX-resistance in MCF-7/ADR cells.	[164]
		100, 200, 300 μM RES + 2 mg/mL DOX	MCF-7/ADR drug resistant cell line	Activation of caspase-8 and caspase-9, inhibition of proliferation and decreased cell viability, miRNA miR-122-5p upregulation and miR-542-3p downregulation, the expression levels of targeted proteins of these miRNAs significantly reduced.	RES chemo-sensitizes drug resistant cancer cell lines.	[65]
		In vitro: 10 mg/L RES + 1 mg/L DOX In vivo: 3 mg/kg DOX i.p. every week and 50 mg/kg RES p.o. for 4 weeks	MCF-7, MCF-7/DOX drug resistant cell lines and nude mice xenograft model	In vitro: PI3K and cleaved caspase-3 upregulation, reduced ratios p-Akt/Akt and p-mTOR/mTOR in MCF-7/DOX cells. In vivo: significant increase in the expression of PI3K and cleaved caspase-3, reduced p70 S6K and Ki67 expression.	In vitro, RES reversed DOX resistance, inhibited DOX-resistant breast cancer cell propagation and metastasis and facilitated cell apoptosis. In vivo, RES and DOX synergistically reduced the tumor volume.	[165]
		20 mg/kg/day RES with 2.5 mg/kg DOX in six injections for 2 weeks	MCF-7 cell line and xenografts in mice	99mTc-MIBI uptake in MCF-7 cells was significantly reduced due to higher apoptosis in tumor cells.	The combination of RES and DOX enhanced the antitumor effect and reduced DOX cardiotoxicity and hepatotoxicity.	[166]
	PTX	1 μM RES + 1, 10, 100 nM PTX	MCF-7, T47D (ERα+) and MDA-MB 231 (ERα−) cell lines	-	RES enhanced cell sensitivity to PTX and lowered the doses of PTX.	[167]

RES: resveratrol; GEM: gemcitabine; 5-FU: 5-fluorouracil; CIS: cisplatin; SOR: sorafenib; DOX: doxorubicin; PTX: paclitaxel.