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Table 1 Apigenin combination therapy with different types of chemotherapy agents

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]