From: Chemoprotective and chemosensitizing effects of apigenin on cancer therapy
Chemotherapy agent | FDA approve of chemodrug | Cancer type | Sample type | Dose of chemodrug | Dose of apigenin | Effects of combined treatment | Target Molecules | Refs. |
---|---|---|---|---|---|---|---|---|
5-Fluorouracil | Approved in 2000 | Human breast cancer | MDA-MB-453 cell line | 90 µM | > 10 µM | More inhibition of the cell proliferation and more induction of the apoptosis compared with the chemodrug alone | ↓ ErbB-2 ↓ AKT ↑ Caspase-3 | [44] |
Head and neck squamous cell carcinoma | SCC25 cell line | 10–100 µM | 5 µM | More inhibition of the cell proliferation compared with the chemodrug alone | NA | [51] | ||
Human pancreatic cancer | BxPC-3 cell line | 50 µM | 13 µM | More inhibition of the cell proliferation compared with the chemodrug alone | NA | [52] | ||
Hepatocellular carcinoma | SK-Hep-1 and BEL-7402 cell lines and HCC xenograft model | 100 μg/ml for cell lines treatment and 20 mg/kg for in vivo treatment | 4 μmol/L for cell lines treatment and 20 mg/kg for in vivo treatment | In HCC cells significantly enhanced the cytotoxicity of 5-FU and increased levels of ROS and a decrease in the mitochondrial membrane potential In vivo, combined treatment significantly inhibited the growth of HCC xenograft tumors | ↑ Caspase-3 ↑ PARP ↓ Bcl-2 | [53] | ||
Induced oral mucositis by 5-FU as the common side effect of 5-FU | Syrian hamster model | 60 mg/kg body weight | 40 mg/kg | Enhancement of the healing of oral mucositis induced by 5-fluorouracil | NA | [55] | ||
Solid Ehrlich carcinoma | Swiss albino male mice | 20 mg/kg | 100 mg/kg | Significant decrease in tumor volume, tissue glutathione peroxidase and total antioxidant capacity and alleviated the histopathological changes with significant decrease of Ki-67 proliferation index compared to vehicle treated SEC control group | ↑ Beclin-1 ↑ Caspases 3, 9 ↑ JNK ↓ Mcl-1 | [56] | ||
Human leukemia | TIB-152, TIB- 202, CCL-119 and CCL-243 cell lines | 0.01–10 µM | 10 µM | Synergistic decrease in ATP levels, induction of cell-cycle arrest and apoptosis | ↑ Caspase-3 ↓ ATP | [3] | ||
Human colorectal cancer | HCT-15 and HT-29cell lines and CRC xenograft model | 5 mM | 7.5 mM | Enhanced anti-proliferative effect Induction of cellular arrest and/or apoptosis Inhibition of angiogenesis | ↑AMPK ↑ ROS ↓ COX-2 ↓ HIF-1α | [61] | ||
Cetuximab | Approved in 2004 | Head and neck squamous cell carcinoma | Cal27 and LICR-HN1 cell lines | 15 nM | 17.5 mM | Reduced the cells survival | NA | [66] |
Head and neck squamous cell carcinoma | LICR-HN5 R9.1 and SC263 10.2 cell lines | 15 nM | 25 mM | Inhibited cell proliferation | ↑ S100A8 ↑ PLAU in SC263 10.2 ↓ PLAU in LICR-HN5 R9.1 ↓ CST6 ↓ FOSL1 ↓ VIM | [68] | ||
Human nasopharyngeal carcinoma | HONE1 and CNE2 cell lines, NPC nude mice | 0.25 mg/ml for cell lines treatment 50 mg/kg/day for in vivo treatment | 50 µM for cell lines treatment 0.8 mg/mouse/day for in vivo treatment | Increased the anti-tumor ability of cetuximab Enhanced the effect of cetuximab on the induction of apoptosis and cell cycle arrest Elevated the ability of cetuximab to inhibit the EGFR signaling pathway | ↓ p-EGFR ↓ p-AKT ↓ p-STAT3 ↓ Cyclin D1 | [75] | ||
Cisplatin | Approved in 1978 | Murine melanoma | B16-BL6 cell line | 2 mg/kg | 25 mg/kg | More inhibition of the cell proliferation compared with the chemodrug alone | NA | [81] |
Human laryngeal carcinoma | Hep-2 cell line | 5 µg/ml | 10, 40, 160 µM | Apigenin enhanced the cisplatin-induced suppression of Hep-2 cell growth | ↓ GLUT-1 ↓ p-AKT | [82] | ||
Human normal renal cells | Immortalized human renal proximal tubular epithelial (HK-2) cells | 40 µM | 5, 10, 20 µM | Apigenin improved cisplatin-induced apoptosis | ↓ caspase-3 ↑ PARP ↓ P53 ↑ PI3K/AKT | [86] | ||
Human cervical, alveolar basal epithelial, colon, non-small cell lung, and breast cancers | HeLa, A549, HCT 116, H1299, and MCF-7 cell lines | 2.5, 5, 10 µM | 30 µM | Apigenin enhances the cytotoxic effect of cisplatin and cisplatin-induced apoptosis | ↑ MAPK ↑ P53 | [87] | ||
Male BALB/c mice | Kidney tissue | 20 mg/kg | 5, 10, 20 mg/kg | Apigenin attenuated cisplatin-induced kidney injury through anti- oxidant and anti-inflammatory effects | ↓ TNF-α ↓ IL-1β ↓ TGF-β ↓ CYP2E1 ↓ p-NF-κB p65 ↓ p-p38 MAPK | [88] | ||
Female Wistar Albino mice | Kidney tissue | 7.5 mg/kg | 3 mg/kg | Apigenin attenuated cisplatin-induced kidney injury through anti- oxidant and anti-inflammatory effects | ↓ caspase-3 ↓ TNF-a ↓ IL-6 | [90] | ||
Human breast cancer | MDA-MB-231 and HCC1806 cell lines | 6 μg/ml for MDA-MB-231 and 12 μg/ml for HCC1806 | 14 μg/ml for MDA-MB-231 and 8 μg/ml for HCC1806 | Induction of cell apoptosis | ↓ hTERT ↓ Hsp90 ↓ p23 | [91] | ||
Human prostate cancer | PC3 cell line | 15 mM | 7.5 mM | Induction of the cell cycle arrest | ↓ p-PI3K ↓ p-Akt ↓ NF-kB ↑ p21 ↑ CDK-2 ↑ CDK-4 ↑ CDK-6 | [92] | ||
Human ovarian adenocarcinoma | SKOV-3 and SKOV-3/DDP cell lines | 2 µM | 50 µM | Induction of the cell cycle arrest and apoptosis promotion | ↓ cyclin D ↓ cyclin B ↓ cyclin E ↓ Bcl-2 ↓ Mcl-1 ↑ Caspase-3 activity | [93] | ||
Cyclophosphamide | Approved in 1959 | Human leukaemia | Jurkat CCRF-CEM THP-1 KG-1a cell lines | 10 µM | 10–50 µM | Induction of the cell cycle arrest and apoptosis promotion | ↑ Caspase-3 activity ↑ Caspase-8 activity ↑ Caspase-9 activity ↑ γH2AX foci ↓ ATP | [99] |
Doxorubicine | Approved in 1974 | Human hepatocellular carcinoma | BEL-7402/ADM and EL-7402 cell line | 10 µM | 10 µM | Induction of the cell cycle arrest and apoptosis promotion | ↓ Nrf2 ↓ PI3K/AKT | [101] |
Human hepatocellular carcinoma | BEL-7402/ADM cell line | 8 µg/ml | 10 µM | Induction of the cell cycle arrest and apoptosis promotion | ↓ Nrf2 ↑ miR-101 | [102] | ||
Human hepatocellular carcinoma | BEL-7402/ADM cell line | 2 µM | 10 µM | Induction of the cell cycle arrest and apoptosis promotion | ↓ ATG7 ↑ miR-520b | [103] | ||
Human prostate cancer | C4-2B and TaxR cell lines | 20 nM | 10 mM | Induction of the cell cycle arrest and apoptosis promotion | ↓ ABCB1 | [107] | ||
Human uterine sarcoma | MES-SA/Dx5 | 2–8 µM | 10 µM | Induction of the cell cycle arrest and apoptosis promotion | ↓ ABCB1 | [109] | ||
Human breast cancer | MCF-7/ADR cell line | 20 µg/ml | 100 µM | Induction of the cell cycle arrest and apoptosis promotion | ↓ ABCB1 ↓ STAT3 | [110] | ||
Human leukaemia | Jurkat CCRF-CEM THP-1 KG-1a cell lines | 10 µM | 10–50 µM | Induction of the cell cycle arrest and apoptosis promotion | ↑ Caspase-3 activity ↑ Caspase-8 activity ↑ Caspase-9 activity ↑ γH2AX foci ↓ ATP | [111] | ||
Human hepatocellular carcinoma | HepG2 cell line | 1 µM | 50 µM | Glycolysis inhibition | ↓ HK2 ↓ LDHA | [114] | ||
Human ovarian adenocarcinoma | SKOV-3 cell line | 0.5 µM | 26 µM | Induction of the cell cycle arrest and apoptosis promotion | ↑ Caspase-9 activity ↑ COX-2 ↑ Bcl-2 | [115] | ||
Gemcitabine | Approved in 1996 | Human pancreatic cancer | BxPC-3 cell line | 10 µM | 13 µM | More inhibition of the cell proliferation compared with the chemodrug alone | NA | [52] |
Human pancreatic cancer | MiaPaCa-2 and AsPC-1 cell lines | 10 µM | 25 or 50 µM | Induction of the cell cycle arrest and apoptosis promotion | ↓ NFκB ↓ AKT | [118] | ||
Human pancreatic cancer | CD18 and AsPC-1 cell lines | 10 µM | 25 µM | Induction of the cell cycle arrest and apoptosis promotion | ↓ AKT | [119] | ||
Navitoclax | Not approved | Human colon cancer | DLD1, HCT116, HCT-8, HT29 and SW48 cell lines | 1 µM | 20 µM | Induction of apoptosis | ↑ Mcl-1 ↑ Bim ↑ Bax ↓ AKT ↓ ERK | [122] |
EGFRm tumors | H1975, HCC827, H1650, H3255, SK-MEL-28 cell lines | 2 µM | 15 µM | Inhibition of cell growth and proliferation | ↓ EGFR ↑ Noxa ↓ AKT ↓ FOXO3a | [123] | ||
Paclitaxel | Approved in 2002 | Human cervical epithelial, lung epithelial, and negroid hepatocyte carcinomas | HeLa, A549 and Hep3B cell lines | 4 nM | 15 µM | Induction of apoptosis | ↓ SOD ↑ Caspase-2 activity | [127] |
Human hepatocellular carcinoma | HepG2 cell line | 6.5, 25, 100 nM | 40 µM | Reverse hypoxia-induced drug resistance | ↓ HIF-1a ↓ AKT ↓ HSP90 | [128] | ||
Human ovarian adenocarcinoma | SKOV-3 cell line | 5 nM | 10 µM | Induction of the cell cycle arrest and apoptosis promotion | ↓ SOD ↑ ROS ↑ Caspase-3 activity ↑ Bax ↓ Bcl-2 | [130] | ||
Sorafenib | Approved in 2005 | Human hepatocellular carcinoma | HepG2 cell line | 5 μM | 50 μM | Induction of the cell cycle arrest and apoptosis promotion | ↑ caspase-3 ↑ caspase-8 ↑ caspase-10 ↑ BID ↑ p21 ↑ p16 | [132] |
Tamoxifen | Approved in 2000 | Human breast cancer | Xenograft female albino Wistar rats | 50 mg/kg | 100 and 200 mg/kg | Increased the activity of anti-oxidant enzymes and reduced angiogenesis | ↑ SOD ↑ GPx ↑ CAT ↓VEGF | [134] |
Human breast cancer | MCF-7 cell line | 100 nM | 10 μM | Inhibition of cell growth | ↓ ERα ↓ AIB1 | [135] | ||
Abivertinib | Not approved | Human DLBCL lymphoma | U2932 and OCI-LY10 cell lines and DLBCL xenograft BALB/c nude mice model | 156 nM for cell lines and 30 mg/kg for xenograft model | 2.5 μM for cell lines and 2 mg/kg for xenograft model | Induction of the cell cycle arrest and apoptosis promotion | ↓ BCL-XL ↓ PI3K/mTOR ↓ p-GS3K-β ↓ BTK ↑ caspase-3 ↑ caspase-8 | [137] |
Apo2L-TRAIL | Not approved | Human prostate cancer | DU145 and LNCaP cell lines | 50 ng/ml | 20 μM | Induction of apoptosis | ↓ ANT2 ↑ DR5 | [139] |
Chlorambucil | Not approved | Human leukemia | Jurkat CCRF-CEM THP-1 KG-1a cell lines | 0.01–10 µM | 50 µM | Synergistic decrease in ATP levels, induction of cell-cycle arrest and apoptosis | ↑ Caspase-3 activity ↑ Caspase-8 activity ↑ Caspase-9 activity ↑ γH2AX foci ↓ ATP | [99] |
Gefitinib | Approved in 2003 | Human NSCLC | NCI-H1975 and 95-D cell lines | 40 µM | 40 µM | Induction of the cell cycle arrest and apoptosis promotion | ↑ Caspase-3 activity ↑ PARP-1 ↓ Bcl-2 ↑ BIM ↑ Bax ↓ p-AMPK-α | [141] |
IFN-γ | Approved in 1991 | Human cervical cancer | HeLA cell lines | 100 ng/ml | 10 µM | Induction of the cell cycle arrest and apoptosis promotion | NA | [130] |