Table 1.
Flavonoids improve the chemosensitivity of chemotherapeutic drugs in cancer.
| Molecules | Origins | Experimental Approaches | Key Results | References |
|---|---|---|---|---|
| Apigenin | Synthetized | MDA435/LCC6 and P388 cells Cell proliferation assay ATPase assay |
Enhanced the cytotoxicity of paclitaxel (PTX), doxorubicin (Dox), daunomycin (DM), vincristine (VCR), and vinblastine, resulting in a reduction of IC50 by 5–50 times | [11] |
| Purchased | Parental human HCC cells (BEL-7402) and BEL-7402/ADM cells MTT assay Cell cycle analysis Real-time quantitative PCR Western blot analysis In vivo xenograft studies |
Sensitized Dox-resistant BEL-7402 (BEL- 7402/ADM) cells to Dox Increased intracellular concentration of Dox Reduced Nrf2 expression APG + Dox (in vivo) inhibited tumor growth, reduced cell proliferation, and induced apoptosis more substantially when compared with Dox treatment alone |
[12] | |
| Purchased | Human pancreatic cancer cell line BxPC-3 Human pancreatic ductal epithelium (HPDE) cells Western blot analysis MTS cell proliferation assay |
APG (13 μM) + gemcitabine (Gem) (13 μM) inhibited cell proliferation APG (11–19 μM) + Gem (10 μM) inhibited growth by 59–73% Enhanced the anti-proliferative activity of chemotherapeutic drugs |
[13] | |
| Purchased | Human pancreatic cancer cell lines AsPc-1, Panc-1, and MiaPaCa-2 MTT assay Cell apoptosis assay Western blot analysis In vitro IKK-β kinase activity assay Xenograft model |
Reduced cell growth Induced cell apoptosis Down-regulated the TNF-α-induced NF-κB DNA binding activity Suppressed pancreatic cancer growth and IKK-β activation in nude mice xenograft |
[14] | |
| Purchased | Laryngeal carcinoma Hep-2 cell line RT-PCR Cell counting Kit-8 (CCK-8) system Western blot analysis |
Enhanced the cisplatin (CP)-induced suppression of Hep-2 cell growth in a concentration- and time-dependent manner Reduced the levels of GLUT-1 mRNA and GLUT-1 and p-Akt proteins in CP-treated Hep-2 cells in a concentration and time-dependent manner |
[15] | |
| Purchased | Laryngeal hep-2 carcinoma cell line Nude mouse model of laryngeal carcinoma Western blot analysis |
Improved xenograft radio-sensitivity Reduced the expression of PI3K mRNA, Akt, and GLUT-1 after X-ray radiation |
[16] | |
| Purchased | Tumor xenografts in nude mice SK-Hep-1 and BEL-7402 cells MTT assay Annexin V/PI assay Western blotting analysis Cellular ROS detection |
Enhanced the cytotoxicity of 5-FU in HCC cells APG + 5-fluorouracil (5-FU) (in vivo) inhibited HCC xenograft tumor growth APG + 5-FU increased the levels of reactive oxygen species (ROS) APG + 5-FU decreased the mitochondrial membrane potential (ΔΨm) APG + 5-FU decreased Bcl-2 expression |
[17] | |
| Purchased | Human renal proximal tubular epithelial (HK-2) cells MTT assay Analysis of cell morphology and cell cycleCaspase-3 activity assay Western blot analysis ROS production assay |
Inhibited the CP-induced apoptosis of HK-2 cells Induced cell cycle arrest Inhibited caspase-3 activity and PARP cleavage Reduced CP-induced phosphorylation and expression of p53 Promoted the CP-induced Akt phosphorylation |
[18] | |
| Purchased | 80 Swiss albino male mice ELISA Quantitative real-time RT-PCR Histopathological and immunohistochemical analysis |
APG alone or combined with 5-FU Increased Beclin-1 levels, caspase-3 and -9, and JNK activities, decreased tumor volume, Mcl-1expression, and total antioxidant capacity, alleviated histopathological changes, and decreased Ki-67 proliferation index |
[19] | |
| Not reported | BEL-7402 and BEL-7402/ADM cells TUNEL assay qRT-PCR Annexin V-FITC/PI apoptosis assay Western blot analysis |
Reversed Dox sensitivity Induced the caspase-dependent apoptosis in BEL-7402/ADM cells Induced the miR-101 expression |
[20] | |
| Not reported | Human hepatocellular carcinoma (HCC) and adjacent normal tissue specimens qRT-PCR MTT assay Western blot analysis In vivo xenograft studies |
Enhanced Dox sensitivity Induced miR-520b expression Inhibited ATG7-dependent autophagy in BEL-7402/ADM cells Inhibited hepatocellular carcinoma xenograft growth |
[21] | |
| Purchased | Ovarian cancer-sensitive cell line SKOV3 Ovarian cancer drug-resistant cell line SKOV3/DDP MTT assay PCR test Western blot test Apoptosis test |
Enhanced the chemosensitivity of ovarian cancer-sensitive cells and drug-resistant cells Induced the apoptosis of ovarian cancer cells by down-regulating the Mcl-1 gene |
[22] | |
| Quercetin | Purchased | DB-1 melanoma and SK Mel 28 cell lines Western blot analysis Annexin V-FITC staining RNA isolation and RT-PCR Immunocytochemistry siRNA transfection |
Induced a redistribution of ΔNp73 in the cytoplasm and nucleus Que + temozolomide (TMZ) abolished drug insensitivity and caused a more than additive induction of apoptosis |
[23] |
| Not reported | Human esophageal cancer cells (EC9706 and Eca109) MTT assay Annexin V-FITC/propidium iodide (PI)-stained fluorescence-activated cell sorting (FACS) Western blot analysis |
Que + 5-FU inhibited growth and stimulated apoptosis in EC9706 and Eca109 esophageal cancer cells compared to Que | [24] | |
| Purchased | MCF-7 and MCF-7/Dox cells MTT assay Flow cytometry Matrigel invasion assay Western blot analysis |
Increased intracellular concentration of Dox Improved Dox cytotoxicity Que + Dox inhibited cell proliferation and invasion and suppressed HIF-1α and P-gp expression |
[25] | |
| Not reported | Human ovarian cancer cell lines, SKOV-3, EFO27, OVCAR-3, and A2780P Evaluation of quercetin toxicity SRB staining |
Inhibited proliferation and increased sensitivity of ovarian cancer cells to CP and PTX | [26] | |
| Purchased | U251 and U87 human glioblastoma cells MTT assay Flow cytometry Western blot analysis |
Que (30 μmol/L) + TMZ (100 μmol/L) inhibited cell viability and enhanced TMZ inhibition Que did not affect the caspase-3 activity and cell apoptosis, whereas combined with TMZ, it increased the caspase-3 activity and induced cell apoptosis. |
[27] | |
| Purchased | MCF-7 cells and MCF-7/Dox cells MTT assay Flow cytometry |
Que + Dox inhibited cell proliferation and invasion Que + Dox increased cell apoptosis Que + Dox up-regulated PTEN expression Que + Dox down-regulated p-Akt expression |
[28] | |
| Purchased | Lung cancer cells (A549 and H460 cells) Western blot analysis |
Reduced cell viability Suppressed HSP70 expression Improved Gem-induced cell death linked to increased caspase-3 and caspase-9 activities Que + Gem down-regulated HSP70 expression more significantly than treatment with Que or Gem alone |
[29] | |
| Not reported | BEL-7402 and multidrug-resistant cell line BEL/5-FU MTT assay Flow cytometry Real-time PCR Western blot analysis |
Increased intracellular accumulation of Dox Increased sensitivity of BEL/5-FU cells to chemotherapeutic drugs Down-regulated the expressions of ABCB1, ABCC1, and ABCC2 Inhibited the functions and expressions of ABCB1, ABCC1, and ABCC2 efflux pump |
[30] | |
| Purchased | Human prostate cancer cell line PC3 MTT assay Western blot analysis Flow cytometry |
Inhibited c-met expression and the downstream PI3K/AKT pathway Que + Dox promoted the Dox-induced cell apoptosis through the mitochondrial/ROS pathway |
[31] | |
| Purchased | Human pancreatic cancer cell lines Transfection of small interfering RNA MTT assay Western blot analysis Cell cycle measurement |
Attenuated RAGE expression to facilitate cell cycle arrest, autophagy, apoptosis, and GEM chemosensitivity in MIA Paca-2 GEMR cells | [32] | |
| Purchased | Human prostate cancer (PC-3) cell lines Nude male BALB/c mice MTT assay Intracellular ROS content assays RNA extraction and qRT-PCR Western blot analysis Immunohistochemistry |
Que + PTX inhibited cell proliferation, increased apoptosis, arrested cell cycle at the G2/M phase, inhibited cell migration, induced ER stress, and increased ROS generation Que + PTX exerted the most beneficial therapeutic effects (in vivo) Increased the cancer cell-killing effects of PTX (in vivo) |
[33] | |
| Not reported | MCF 7 cells MTT assay Flow cytometry qRT-PCR ELISA |
Quer + 5-FU improved apoptosis by increasing the gene expression of Bax and p53 and caspase-9 activity and decreasing Bcl2 gene expression Quer + 5-FU decreased colony formation |
[34] | |
| Purchased | MDA-MB-231 human breast cancer cell line MTT assay Flow cytometry qRT-PCR Western blot analysis |
Decreased cell viability Que (95 μM) + docetaxel (7 nM) up-regulated p53, increased BAX levels, and decreased levels of BCL2, pERK1/2, AKT, and STAT3 proteins |
[35] | |
| Kaempferol | Purchased | Human myelogenous leukemia K562 cells and the adriamycin-resistant variant K562/A cells MTT assay Annexin V/PI analysis PCR array |
Kae + Que inhibited the growth of both cells Kae + Que increased the sensitivity of both cells Kae + Que induced apoptosis Kae + Que influenced the expression of drug transporter genes |
[36] |
| Purchased | LS174 colon cancer cells MTT assay Colony formation assay Spheroid generation Sensitization assay Measurement of ROS Western blot analysis qRT-PCR |
Chemo-sensitized 5-FU-resistant LS174-R cells Blocked the production of ROS and modulated the expression of JAK/STAT3, MAPK, PI3K/AKT, and NF-κBKae + 5-FU exerted a synergistic inhibitory effect on cell viability Kae + 5-FU enhanced apoptosis and induced cell cycle arrest in chemo-resistant and sensitive cells |
[37] | |
| Purchased | Human colorectal cancer cell line HCT8 5-FU-resistant cell line HCT8-R CCK-8 assay qPCR assay Western blot analysis Clonogenic assay |
Reversed the drug resistance of HCT8-R cells to 5-FU Reduced glucose uptake and lactic acid production in drug-resistant colorectal cancer cells Promoted the expression of microRNA-326 in colon cancer cells Reversed the resistance of colorectal cancer cells to 5-FU |
[38] | |
| Myricetin | Purchased | Esophageal carcinoma EC9706 cells Colony formation assays Flow cytometry Western blot analysis Nude mouse tumor xenograft model |
MYR + 5-FU suppressed cell survival fraction and proliferation, and increased cell apoptosis MYR + 5-FU decreased survivin, cyclin D, and Bcl-2, and increased the expression level of caspase-3 and p53 MYR + 5-FU reduced the growth rate of tumor xenografts in mice |
[39] |
| Purchased | A2780 and OVCAR3 ovarian cancer cells MTT assay Apoptosis assay Boyden chamber assay Western blot analysis |
Induced cytotoxicity, with an IC50 value of 25 μM Induced cell apoptosis, accompanied by the modulation of certain pro- and anti-apoptotic markers Increased paclitaxel cytotoxicity |
[40] | |
| Rutin | Purchased | Human breast cancer MDA- MB-231 cellsCalcein acetoxymethyl accumulation assayRhodamine-123 uptake assay Annexin V and 7-aminoactinomycin D Propidium iodide staining |
Increased the anticancer activity of both chemotherapeutic agents Decreased the activity of adenosine triphosphate binding cassette transporters RTN (20 μM) enhanced cytotoxicity related to cyclophosphamide and methotrexate RTN (20 and 50 μM) arrested the cell cycle at the G2/M and G0/G1 phases, respectively, thus promoting cell apoptosis |
[41] |
| Purchased | Human HCC cell lines qRT-PCR Luciferase reporter assay Cell viability assay Flow cytometry In vivo tumor xenograft |
Attenuated autophagy and BANCR expression in SO-resistant cells Decreased the number of autophagosomes in HepG2/SO and HCCLM3/SO cells Enhanced the efficacy of SO in a xenograft model of HCC in nude mice |
[42] | |
| Hispidulin | Not reported | Human gallbladder carcinoma cell line GBC-SD MTT assay Western blot analysis Flow cytometry Caspase-3 activity assay qRT-PCR In vivo xenograft experiments |
Inhibited the growth of GBC cells Promoted apoptosis in GBC cells Induced cell arrest at the G0/G1 phase Exerted antitumor effect mediated through HIF-1α inhibition Repressed the transactivation activity and expression of HIF-1α Suppressed the HIF-1α expression via AMPK signaling |
[43] |