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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]