Table 4.
The molecular details of the enhanced anticancer activity of combination treatment of flavonoids and conventional chemotherapeutic drugs
| Flavonoids | Combined drugs | Mechanism of action (Combinatorial effect) | Ref. |
|---|---|---|---|
| Delphinidin | Arsenite | Activation of Caspase-8, -9, -3 and Bid; Decrease of GSH and inhibition of NFκB (Enhancement of cytotoxicity of arsenite along with apoptosis induction) | [26] |
| Arsenite | Activation of caspase-8, -9, -3 and Bid; Downregulation of mitochondrial membrane potential (Enhancement of cytotoxicity) | [30] | |
| Casticin | TRAIL | Activation of caspase-3/PARP, induction of DR5 mediated by ROS; Downregulation of Bcl-2, Bcl-xL, survivin, XIAP, cFLIP (Enhancement of apoptosis induction) | [39] |
| Baicalein, 6-hydroxyflavone, 7-hydroxyflavone | Dox/Sim or Mev | Activation of caspase-3 along with DNA fragmentation; Downregulation of proliferating cell nuclear antigen (Synergistic effect on growth inhibition along with apoptosis induction) | [71] |
| Dihydromyricetin | ATRA | Upregulation of CD11b, PU.1, C/EBPβ, activation of p-38-STAT1 pathway (Synergistic effect on cell differentiation) | [100] |
| Quercetin | TMZ | Upregulation of Hsp27 phosphorylation, and caspase-3 activity (Enhancement of apoptosis induction) | [101] |
| Biochanin A | TMZ | Activation of p53; Downregulation of EGFR, phosphorylation of Akt and ERK, c-myc, MT-MMP1, MMP-2, and inhibition of complex IV activity (Enhancement of cell viability inhibition associated with G1 phase arrest) | [104] |
| EGCG | 5-FU | Activation of caspase-3/PARP, and upregulation of Bad; Inhibition of GRP78/ NF-κB/miR-155-5p/MDR1 pathway, downregulation of Bcl-2 (Enhancement of cytotoxicity of 5-FU along with apoptosis induction) | [105] |
| RT | Upregulation of Bax; Downregulation of serum levels of VEGF, HGF, MMP-9/MMP-2 in vivo, downregulation of Bcl-2, inhibition of c-Met, NF-κB, Akt in vitro (Enhancement of cell growth/invasion inhibition and apoptosis induction) | [106] | |
| Luteolin | Dox | Inhibition of Nrf2 mediated signaling (Enhancement of sensitivity to Dox) | [107] |
| PTX | Activation of caspase-8, -3, PARP along with upregulation of Fas; Downregulation of Bcl-xL and inhibition of STAT3 (Enhancement of apoptosis induction and tumor growth inhibition) | [108] | |
| Glabridin | Dox | Inhibition of P-gp expression and function (Increased accumulation of doxorubicin, enhancement of apoptosis induction and S phase arrest) | [109] |
| Quercetin | Curcumin | Induction of BRCA1 expression, and E-cadherin; Downregulation of MMP-9 (Synergistic effect on cell viability and invasion inhibition) | [110] |
| Naringin | PTX/Dox | Upregulation of PTEN; Inhibition of NF-κB signaling, and downregulation of survivin, c-myc (Synergistic effect on cytotoxicity of drugs associated with apoptosis induction, G1 phase arrest and migration inhibition) | [112] |
Abbreviations: 5-FU, 5-fluorouracil; BRCA1, breast cancer type 1 susceptibility protein; C/EBPβ, CCAAT/enhancer-binding protein beta; cFLIP, cellular FLICE-like inhibitory protein; Dox, doxorubicin; DR5, death receptor 5; EGFR, epidermal growth factor receptor; ERK, extracellular signal regulated kinase; GSH, glutathione; HGF, hepatocyte growth factor; Hsp27, heat shock protein 27; MDR1, multidrug resistance 1; Mev, mevastatin; MMP-2, matrix metalloproteinase-2; MMP-9, matrix metalloproteinase-9; MT-MMP1, membrane-type matrix metalloproteinase 1; NF-κB, nuclear factor kappa B; Nrf2, nuclear factor erythroid 2-related factor 2; PARP, poly ADP-ribose polymerase; P-gp, P-glycoprotein; PTEN, phosphatase and tensin homolog deleted on chromosome 10; PTX, paclitaxel, ROS, reactive oxygen species; RT, radiotherapy; Sim, simvastatin; STAT1, signal transducer and activator of transcription 1; STAT3, signal transducer and activator of transcription 3; TMZ, temozolomide; VEGF, vascular endothelial growth factor; XIAP, X-linked inhibitor of apoptosis protein.