Table 2.
Summary of main in vitro and in vivo synergistic effects of combinations of flavonoids and chemotherapeutic compounds against CRC.
| References | Tested molecule | In combination with | Experimental model | Main result | Proposed mechanism |
|---|---|---|---|---|---|
| Horinaka et al., 2006 | Apigenin | TRAIL | CRC cell culture (DLD-1) | Synergistic potentiation of TRAIL-induced apoptosis | Up-regulation of DR5 |
| Shao et al., 2013 | Apigenin | ABT-263 (Navitoclax) | CRC cell culture (HTC-116) and SCID mice bearing HTC-116 xenografts | Synergistic induction of apoptosis, antagonism effect on ABT-263-induced Mcl-1 up-regulation and greater tumour growth inhibition | Down-regulation of Mcl-1, inhibition of PI3K/AKT pathway and ERK phosphorylation |
| Yoshida et al., 2008 | Kaempferol | TRAIL | CRC cell culture (SW480 and DLD-1) | Positive: Increase in apoptotic induction in a kaempferol-dose dependent manner | Up-regulation of DR5 |
| Li et al., 2010 | Chrysin | TNFα | CRC cell culture (HCT-116) | Positive: Increase in cell death | Inhibition of TNFα-induced NF-κβ activation |
| Khan et al., 2012 | Chrysin | Cisplatin | Wistar rats | Positive: Prophylactic effect against colon toxicity | Reducing oxidative stress |
| Ding et al., 2012 | Chrysin | TRAIL | CRC cell culture (HT-29) | Positive: Enhanced TRAIL-induced cell death | Suppression of c-FLIP and up-regulation of DR5 |
| León et al., 2015 | Chrysin | Vanadyl cation | CRC cell culture (HT-29) | Positive: Cell cycle arrest in G2/M phase | Decrease in GSH levels |
| Hwang et al., 2005 | Genistein | 5-FU | CRC cell culture (HT-29) | Synergistic effect on cell growth blocking | Over-expression of pro-apoptotic p53 and p21, down-regulation of Glut-1 and down-regulation of COX-2 |
| Hu et al., 2014 | Genistein | Cisplatin | CRC cell culture (HT-29) | Positive: Inhibited cell growth and induced apoptosis in an additive manner | Inhibition of TK |
| Park et al., 2001 | Genistein | Dexamethasone | CRC cell culture (Colo320 HSR) | Synergistic effect on blocking cell cycle | Increase in p21 levels |
| Son et al., 2013 | Genistein | Radiotherapy | BALB/c mice bearing CT26 xenografts | Positive: Less non-tumorigenic apoptotic cells and improved morphological changes in healthy intestinal tissue | Activation of antioxidant systems |
| Gruca et al., 2014 | Genistein | Radiotherapy | CRC cell culture (HCT-116) | Synergistic effect on clonogenic survival | Enhanced EGFR inhibition and prolonged inhibition of AKT and ERK |
| Kumazaki et al., 2013; Wubetu et al., 2015 | EGCG | 5-FU | CRC cell culture (DLD-1, SW480 and COLO201) | Synergistic growth suppression | Regulation of ABC transporter-related genes |
| Saldanha et al., 2014 | EGCG | Sodium butyrate | CRC cell culture (HT-29) | Synergistic induction of apoptosis | Down-regulation of survivin |
| Ohishi et al., 2002 | EGCG | Sulindac | Azoxymethane colon cancer induction in rats | Synergistic induction of apoptosis | Enhanced inhibition of COX-2 |
| Ambrosini et al., 2008 | Flavopiridol | SN-38 | HCT116 cell line | Synergistic effect on the apoptotic effects of SN-38 | Down-regulation of Rad51 by p53 and Cdk9 inhibition. |
| Darpolor et al., 2011 | Flavopiridol | Irinotecan | Mice xenograft (HCT116) | Improves tumor response | Reduces cytokine activity |
| Fornier et al., 2007 | Flavopiridol | Docetaxel | Phase I trial | Partial responses and a complete response in one patient | Unknown |
| Guo et al., 2006 | Flavopiridol | Docetaxel and 5-FU | Mice xenograft (HCT116) | Significant decrease in a tumor volume | Unknown |
| Motwani et al., 2001 | Flavopiridol | SN-38 | Mouse xenograft model | Flavopiridol enhances a reduction in tumors | The effect is produced by p21 |
| Colombo et al., 2011 | Silymarin | Doxorubicin and paclitaxel | LoVo cell line | Synergistic effect in LoVo cells and additive in LoVo/DX | Low expression of p-gp pump |
| León et al., 2015 | Silymarin | Vanadium compounds | HT29 cell line | Improves cytotoxic effect | Inhibits topoisomerase IB activity and NF-κB |
| Tsai et al., 2015 | Silibinin | Metformin | COLO205 cell line | Reduction cell viability more than 60% | Increase caspase 3 activation and AIF expression |
| Psahoulia et al., 2007 | Quercetin | TRAIL | Caco-2, SW620 and HT29 cell lines | Sensitizes the cells to the treatment | Distribution of death factors in raft domains that are the initiators of apoptosis |
| Xavier et al., 2011 | Quercetin | 5-FU | Co115 and HCT15 cell lines | Enhances apoptosis more than 100 times | The effect is mediated by p53 |
| Osman et al., 2015 | Luteolin | Aspirin | Colorectal cancer in rats | Highly significant reduction in polyps number and size | Enhance inhibition the inflammatory response |
| Chan et al., 2009 | Scutellarin | 5-FU | HCT116 cell line | A significant increase in apoptosis levels | p53-regulated caspase-6 activation mechanism |
| Lee et al., 2008 | Isoliquiritigenin | Cisplatin | Mice xenograft (CT26) | Reduce 79% tumor growth and reduces adverse effects | Mechanism in combination is unknown |
| Ha et al., 2012 | Oroxylin | 5-FU | HT29 cell line and mice xenografts (HT29) | Reduce 66% tumor growth and shows synergistic effects in HT29 cell line | Inhibition of COX-2 gene expression |
| Cheah et al., 2014 | Procyanidins | 5-FU | Caco-2 cell line | Increase cytotoxicity | Unknown |