Table 1 Flavonoids and paclitaxel Co-administration results

1

Ampelopsin (Ovarian cancer)

In vitro: A2780, SKOV3, A2780/paclitaxel cells

In vitro: 25, 50, 100 µM

In vitro: 0.01, 0.1, 1µΜ

In vitro: 48 h

Inhibited proliferation

Induced G0/G1 and S phase arrest

Induced cell apoptosis

Activation of p53

Sensitized resistant ovarian cancer cells to paclitaxel through suppression of survivin expression

[44]

2

Apigenin

(Cervical cancer

In vitro: HeLa

In vitro: 15 µM

In vitro: 4 nM

In vitro: 24 h

Induction of apoptosis via

suppressing the SOD activity led to accumulation of ROS

and cleavage of caspase-2

[48]

3

Baicalein (Ovarian cancer)

In vitro: A2780 cells, SKOV3 cells, and OVCAR

In vitro: 1-1000 µM

In vitro: 1-1000 nM

In vitro: 48 h

Anti-tumor effects

Increased cell apoptosis and necrosis

Increased the caspase-3 activity and its substrate PARP

Inhibited cell proliferation through Akt/b-catenin signaling pathway

[52]

4

1-Chromonyl-5-Imidazolylpentadienone (Breast cancer)

In vitro: MDA-MB-231 and MDA-MB-468, T47D

In vitro: 0.5, 1, and 5 µM

In vitro: 1, 5 and 10 nM

In vitro: 24, 48, and 72 h

Induce the anti-proliferative effect and enhance ROS generation in triple-negative breast cancer cells

[54]

Daidzein (Cervical cancer)

In vitro: A Multi drug resistant cervical carcinoma cell line (KB-V1) and

a drug sensitive cervical carcinoma cell line (KB-3-1)

In vitro: 10 and 30 µM

Not clarified

In vitro: 48 h

Increased the multidrug-resistant (KB-V1 with high P-glycoprotein expression sensitivity to vinblastine and paclitaxel in a dose dependent manner and also it could reduce these anti-cancer drugs relative resistance in KB-V1 cell.

[57]

6

Diosmetin (Lung cancer)

In vitro: A549, H1299, H460, SPC-A1, H441, H1650, Calu‐3

In vivo: 4–6 weeks old female BALB/c nude mice (18–20 g;)

In vitro: 5 µM

In vivo: 50 mg/kg, three times a week

In vitro: 120 nM

In vivo: 10 mg/kg-1, three times a week

In vitro: 48 h

In vivo: 4 weeks

Induced ROS-dependent apoptosis via disruption of the PI3K/Akt/ GSK‐3β/Nrf2 pathway and spares normal cells

[60]

Diosmetin (based on enzyme kinetic, colorectal cancer, and NSCLC)

In vivo: Pooled and mixed human liver microsomes obtained from 25 female and 27 male donors

In vivo: 0.5 to 25 µM

In vivo: 3 to 40 µM

In vivo: 10 min

- Inhibit CYP2C8-mediated paclitaxel metabolism and6-alpha-Hydroxy paclitaxel production.

[61]

7

FD-18 (Breast cancer cells)

In vitro: LCC6 and LCC6MDR

In vivo: 4–6 week old athymic nude mice (Balb/c nu/nu), (15–23 g)

In vitro: 1 µM

In vivo: 45 mg/kg

In vitro: Not clarified

In vivo: 12 mg/kg

In vitro: 5 days

In vivo: 12 times in 22 days

Reverses P-gp-mediated

multidrug resistance in human breast xenograft in vivo.

Increase the accumulation of paclitaxel in LCC6MDR xenograft.

[63]

8

Fisetin (Human liver microsomes)

In vivo: Pooled human liver microsomes

In vivo: 0–25 mM

In vivo: 2.5–25 mM

In vivo: 60 min

Selective reversible and non-competitive inhibitory effect on CYP2C8-mediated paclitaxel hydroxylation

[65]

Fisetin (Lung cancer)

In vitro: A549

In vitro: 10 µM

In vitro: 0.1 µM

In vitro: 24 h

Reduced the migration and invasion of cancer cells and disruption of the actin and vimentin cytoskeleton structure

Inhibition of PI3K/AKT/mTOR signaling pathway

[66]

Fisetin (Lung cancer)

In vitro: A549

In vitro: 10–50 µM

In vitro: 0.1–0.5 µM

In vitro: 24 h

Reduce the A549 cells viability

Prompted low level of apoptosis

Cells did not begin the apoptosis cell process despite appearance of G2/M.

Activated autophagy

[67]

Fisetin (Prostate cancer

In vitro: PC-3, DU-145

In vitro: 0–80 µM

In vitro: 10 µM

In vitro: 24, 48, and 72 h

Stabilized microtubules with binding characteristics far superior than paclitaxel.

Robust up-regulation of microtubule associated proteins MAP-2 and − 4

α-tubulin acetylation

Repressed proliferation, migration, and invasion.

Inhibition of Nudc

[68]

9

Flavopiridol (Breast and colon cancer)

In vitro: MCF-7, MDA-MB-468, HCT116 p21

In vitro:150, and 300 nM

In vitro: 100 nM

In vitro: 24 h

Inhibited the spindle inhibitor-induced endoreduplication and polyploidation

[71]

10

Flavone (Human Osteosarcoma)

In vivo: Male Sprague-dawley rats weighing 270–300 g; U2OS and 143B cells

In vivo: 2, 10, 20 mg/kg

In vivo: 40 mg/kg

In vivo: 0, 0.25, 0.5, 1, 2, 3, 4, 8, 12 and 24 h

Enhancement in paclitaxel bioavailability ,inhibition of cytochrome P450 and the p-glycoprotein efflux pump in the intestinal mucosa

[72, 74]

11

Flavanol, 3-hydroxy flavone and dimethoxyderivatives (Human Osteosarcoma)

In vivo: Inbred male Swiss albino mice weighing 20–25 g (U2OS and 143B cells)

In vivo: 25–200 mg/kg

In vivo: A single dose 10 mg/kg

In vivo: 30 min after flavonol administration

Inhibited TNF-α and IL-1β

Inhibition of nitric oxide and DPPH radical generation

[74]

12

FV-429 (Lung cancer)

In vitro: human NSCLC cell lines A549 and NCI–H460

In vivo: BALB/c nude mice (18–22 g)

In vitro: Not clarified

In vivo: 10 mg/kg

In vitro:

Not clarified

In vivo: 5 mg/kg

In vitro:24 h

In vivo: 2 weeks

Improved the sensitivity of cancerous cells to paclitaxel via the weakening of G2/M phase arrest by deactivating the Wnt pathway

Reprogramed hypoxia-inducible factor 1-alpha-regulated fatty acid metabolism

Inhibited the nuclear translocation of β-catenin and blocks cell cycle

Enhanced in vivo paclitaxel chemo sensitivity via regulating fatty acid metabolism

Yielded better tumor growth suppression

[81]

FV-429 ( Ovarian cancer)

In vitro: SK-OV-3 and A2780

In vivo: 5-6-week old, female, BALB/c nude mice

In vitro: 5, 10 and 20 µM

In vivo: 10 mg/kg

In vitro: 0.2–80 µM

In vivo: 5 mg/kg

In vitro: 24 h

In vivo: 14 days

Improved the sensitivity to paclitaxel via G2/M arrest promotion.

Deteriorated c-Src/Stat3/HIF-1α pathway under hypoxia.

[82]

13

Genistin (Cervical cancer)

In vitro: A Multi drug resistant cervical carcinoma cell line (KB-V1) and

a drug sensitive cervical carcinoma cell line (KB-3-1)

In vitro: 10 and 30 µM

Not clarified

In vitro: 48 h

Increased paclitaxel cytotoxicity and decreased the paclitaxel relative

Have no modulatory effect on anti-cancer drug cytotoxicity, drug transport or P-glycoprotein expression experiments

[159]

14

Glabridin (Breast cancer cells)

In vitro: MDA-MB-231, MDA-MB-231/MDR1, MCF-7, MCF-7/ADR

In vitro: 10 or 30 µM

In vitro: Not clarified

In vitro: 48 h

Reversing drug that targets P-glycoprotein, which could decrease the IC₅₀

[84]

15

Hyperoside (Breast cancer)

In vitro: MDA-MB-231 and HCC1806 cells)

In vitro: 5-100 µg/ml

In vitro: 2–50 nM

In vitro: 24, 48, and 72 h

Improved the effects on apoptosis and caspase-3.

Elevate MDA-MB-231 cells sensitivity

Muted the TLR4-NF-κB signaling

Suppressed apoptosis-related gene and inflammatory cytokine expression

Restoring the TLR4 signaling

[93]

16

Icariin (mechanical allodynia through spinal cord as anti-cancer agent)

In vivo: 3- to 4-month-old male Sprague Dawley rats (220 to 250 g)

In vivo: 25–100 mg/kg

In vivo: 8 mg/kg

In vivo: 22 days

Repressed paclitaxel-induced

neuro-inflammation and mechanical allodynia in a SIRT1-dependent manner [95].

17

Isoxanthohumol (Melanoma)

In vitro:

B16 and A375

In vivo: syngeneic C57BL/6 mice

In vitro: 0-100 µM

In vivo: 20 mg/kg

In vitro:

3.125–25 nM

In vivo: 3 mg/kg

In vitro: 2, 6, 12, 24, 48, 72 h

In vivo: 10 days

Potent anti-melanoma effects and decreased melanoma cell viability

Inhibited melanoma cell division and promoted apoptotic cell death

Snsitized melanoma cells to paclitaxel treatment.

Targeted the PI3K/Akt and MEK-ERK pathways

Inhibited the expression of p70S6K and S6 protein

[99]

18

Isosinensetin (Breast cancer)

In vitro: MX-1 and taxol-resistant MX-1/T cells; MDR1–MDCKII cells for modeling epithelial cells

In vitro: 2 fold of IC50 (IC50: 8.4 µM µM)

In vitro: 75 µM

In vitro: 4 h

Increase taxol cytotoxicity

Inhibitory effects on P-glycoprotein

[101]

19

Kaempferol (Cervical cancer)

In vitro: A Multi drug resistant cervical carcinoma cell line (KB-V1) and

a drug sensitive cervical carcinoma cell line (KB-3-1)

In vitro: 10 and 30 µM

Not clarified

In vitro: 48 h

Enhanced the multidrug resistance sensitivity with high P-glycoprotein expression

Improve the cytotoxic effects and decrease the relative resistance of paclitaxel

[57]

20

Luteolin (Oesophageal cancer)

In vitro: TE-1, EC109, TE-1/PTX, and EC109/PTX cells

In vivo: Adult female 4-week-old athymic BALB/c nude

mice (15–20 g)

In vitro: 0–40 µM/L

In vivo: 50

mg/kg/day

0-256 nM

In vitro: 72 h

In vivo: 29 days

Anti-stemness effect was due to reduction of SOX2 expression

Inhibition of PI3K/AKT pathway and UBR5-mediated SOX2 protein

Inhibitory effect on cell migration by affecting EMT process

[107]

Luteolin (Oesophageal cancer)

In vitro: TE-1 and EC109 cells

In vivo: 4-week-old female BALB/c nude mice (13–14 g)

In vitro: 20 and 30 µM

In vivo: 50 mg/kg/day,

In vitro: 2, 5, and 15 nM

In vivo: 5 mg/kg/2 day

In vitro: 24 and 48 h

In vivo: 19 days

Inhibition of cell migration and EMT processes may be related to the SIRT1 inhibition

Induce mitochondrial apoptosis with ROS/JNK pathway

[108]

Luteolin (Breast cancer)

In vitro: MDA-MB-231

In vitro: 2 µM

10 nM

48 h

Inhibited breast cancer stemness and improves chemosensitivity via Nrf2-Mediated Pathway.

[109]

Luteolin (Breast cancer)

In vitro: MDA-MB-231

In vivo: 6-week-old female athymic nude mice (BALB/cAnN.Cg-Foxnlnu/CrlNarl)

In vitro:0–15 µM

In vivo: 3 mg/kg, 3 times/week

In vitro: 40 nM

In vivo: 1 mg/kg,, 3 times/week

In vitro: 24, and 48 h

In vivo: 28 days

Activation of caspase-8 and caspase-3 and increasing Fas expression.

Blocking of the STAT3 transcription factor

[110]

Luteolin (Oral squamous cell carcinoma)

In vitro: SCC-4

In vivo: 5-6-week-old male nude mice (BALB/c nu/nu) (18–22 g)

In vitro: 0-100 µM

In vivo: 5 and 10 mg/kg/2days

In vitro: 0.3 nM

In vivo: 1 mg/kg/2 days

In vitro: 24, 48, and 72 h

In vivo: 44 days

Decreased the SCC-4 cells viability,

induced apoptosis by decreasing the expression of cyclin-dependent kinase (CDKs), cyclins, and phosphor- retinoblastoma (p-Rb) anti-apoptotic protein, echanced the expression of proapoptotic proteins and stimulated caspase 9 and 3, with a concomitant increase in the levels of

cleaved poly-ADP-ribose polymerase (PARP)

[105]

21

Morin (Prostate cancer)

In vitro: DU145 and PC-3

In vivo: nude mice

In vitro: 50 µM

In vivo: 50 mg/kg

In vitro: 0-100 nM

In vivo: 50

 µg/kg

In vitro: 48 h

In vivo: 20 days

Improve the chemo sensitivity via restoring the miR-155-suppressed expression of GATA3

[113]

22

Myricetin (Ovarian cancer)

In vitro: A2780 and OVCAR3

In vitro: 5 µM

In vitro: 100 nM

In vitro: 48 h

Enhanced the paclitaxel efficacy by targeting multidrug resistance protein-1

[115]

23

Naringenin (Prostate cancer)

In vitro: PC-3 and LNCaP cells

In vitro: 50 µM

In vitro: : 10 µM

In vitro:48 h

Induced apoptosis via regulation of PI3K/AKT and suppression of ERK1/2, P38 and JNK signaling pathways.

Induced the MMP loss and ROS generation for intrinsic apoptotic

Enhance the paclitaxel efficiency to suppress the cancer cells progression

[117]

24

Naringin (Prostate cancer)

In vitro: DU145, PC3, and LNCaP

In vitro150 mM

In vitro: 5 nM

In vitro: 72 h

Inhibits cell survival and cell migration

Induces apoptosis

Increases cell cycle arrest

Upregulates PTEN and inhibits NF-kB signaling

[120]

25

Nobiletin (Lung cancer)

In vivo: A549/T

xenograft model: Male Sprague–Dawley rats (8 weeks old, 180 g), and

Balb/c-nude mice (8 weeks old, 20 g)

In vivo: 12.5, 25, 35, and 50 mg/kg

In vivo: 10.5 and 15 mg/kg

In vivo: Every 3 days for 21 days

Reversed paclitaxel resistance in multi-drug resistance

Increasing the tumor paclitaxel concentration and modulating Nrf2/AKT/ERK pathways

[124]

26

Oroxylin A (Ovarian cancer)

In vitro:

NCI/ADR-RES

In vivo: Male

Sprague-Dawley rats (280–300 g)

In vitro: 0–40 µM

In vivo: 30 mg/kg

In vitro: 5 µM

In vivo: 15 mg /kg

In vitro: 72 h

In vivo: 0.25, 0.5, 0.75, 1, 2, 4, 8, 12, and 24 h

Inhibitory effect on P-glycoprotein mediated drug efflux

[126]

Oroxylin A (Breast cancer)

MX-1 and taxol-resistant MX-1/T cells; MDR1–MDCKII cells for modeling epithelial cells

In vitro: 2 fold of IC50 (IC50: 155.6 µM)

In vitro: 75 µM

In vitro: 4 h

Increase taxol cytotoxicity and decrease the cell viability

Inhibitory effects on P-glycoprotein

[101]

27

Quercetin (Cervical carcinoma)

In vitro: A Multi drug resistant cervical carcinoma cell line (KB-V1) and

a drug sensitive cervical carcinoma cell line (KB-3-1)

In vitro: 10 and 30 µM

Not clarified

In vitro: 48 h

Stimulate the accumulation, and decreased the efflux of Rh123, in KB-V1 cells dose dependently

Reduction in Rh123 efflux from cells and resulted in an increase in intracellular Rh123 retention

[57]

Quercetin (Gastric adenocarcinoma)

In vitro: AGS-cyr61

In vitro: 0-200 µM

In vitro: 0-100 nM

In vitro: 24 h

Reduced multidrug resistance-associated protein 1 and nuclear factor (NF)-kappa

B p65 subunit levels

Reversed multidrug resistance

Reserved colony formation and induced caspase-dependent apoptosis

Suppress migration and down-regulated

EMT-related proteins in AGS-cyr61

[129]

Quercetin (Choriocarcinoma Cells)

In vitro: JAR and JEG3

In vitro: 0-100 µM

In vitro: 2.5 and 5 µM

In vitro: 48 h

Inhibition on development of choriocarcinoma cells were mediated via PI3K/AKT and MAPK signal transduction cascades

Decreased proliferation and induced cell death, with an enhancement in the cell cycle sub-G1 phase.

Induced mitochondrial dysfunction significantly reduced MMP

and increased the production of ROS

Reserved the phosphorylation of AKT, P70S6K, and S6 proteins, whereas it enhanced

phosphorylation of ERK1/2, P38, JNK and P90RSK proteins

[130]

Quercetin (Basophilic leukemia)

In vitro: RBL-2H3

In vivo: adult male Sprague-Dawley rat (180–220 g) and mice (22–25 g)

In vitro: 3, 10, and 30 µmol/L

In vivo: 20 and 60 mg/kg

In vitro: 10 µmol/L

In vivo: 2 mg/kg

In vitro: 24 h

In vivo: 40 days

Improved the neuropathic pain by stabilizing mast cells and blocking of the PKCε-dependent TRPV1activation

[131]

Quercetin (Colorectal cancer)

In vitro: HCT116

In vitro:0-100 µM

In vitro: 0–400 nM

In vitro: 24, 48, 72 h

Inhibited the taxol activity to induce G2/M arrest

Reduce the cancer cells clonogenicity and survival

[132]

28

Sciadopitysin (Breast cancer)

In vitro: MX-1 and taxol-resistant MX-1/T cells; MDR1–MDCKII cells for modeling epithelial cells

In vitro: : 2 folds of IC50 (IC50: 106.8 µM)

In vitro: : 75 µM

In vitro: 4 h

Increase taxol cytotoxicity and decrease the cell viability

Inhibitory effects on P-glycoprotein

[101]

29

Silibinin (Breast cancer)

In vitro: MCF-7

In vitro: 1-400 µM

In vitro: 1-200 nM

In vitro: 24 h

Decreasing in anti-apoptotic Bcl-2 level

Increasing in pro-apoptotic Bax, P53, BRCA1 and ATM mRNA levels

[140]

Silibinin (Renal cancer)

In vitro: 786-O

In vivo: 5–6 week-old

immuno-deficient nude mice (ICR nu/nu mice)

(18–22 g)

In vitro: 0–50 µM

In vivo: 100 and 200 mg/kg/day

In vitro:0-200 nM

In vivo: -

In vitro: 24, 48 h

In vivo:44 days

Decreased MMP-2, MMP-9, u-PA, p-p38, and p-Erk1/2 expressions in a concentration-dependent

manner

Decreased the NF-kB, c-Jun and c-Fos

Enhanced the chemosensitivity of paclitaxel

[141]

30

Sinensetin (Breast cancer)

In vitro: MX-1 and taxol-resistant MX-1/T cells; MDR1–MDCKII cells for modeling epithelial cells

In vitro: : 2 folds of IC50 (IC50: 37.8 µM)

In vitro: : 75 µM

In vitro: 4 h

Increase paclitaxel cytotoxicity

Inhibitory effects on P-glycoprotein

[101]

31

Tangeretin (Ovarian and lung cancer)

In vitro: A2780, A2780/T, A549, A549/T

In vitro: 0.83, 2.51, 7.53 µM

In vitro: 1 µM to 0.03 nM, 10 µM to 0.3 nM, or 100 µM to 3 nM

In vitro: 24, 48, 72 h

Increased the chemotherapeutic agents efficacy in ABCB1 overexpressing cells

Induced apoptosis

Arrested resistant cells at the G2/M-phase

Exerted synergistic effect in multidrug resistance cells

[83]

Tangeretin (Breast cancer)

In vitro: MX-1 and taxol-resistant MX-1/T cells; MDR1–MDCKII cells for modeling epithelial cells

In vitro: 2 folds of IC50 (IC50: 25.3 µM)

In vitro: 75 µM

In vitro: 4 h

Increase paclitaxel cytotoxicity and decrease the

cell viability

Inhibitory effects on P-glycoprotein

[101]

32

TMF (Colon and lung cancer)

In vitro: Caco-2 and SK-MES-1/PT4000

In vitro: 50–400 µM

In vitro: 0-100 µM

In vitro: 72 h

Improved the bioavailability and enhance paclitaxel cytotoxicity and apical to basolateral transport

Apical loading of TMF increased the sensitivity of paclitaxel to overexpressing P-glycoprotein on basolateral side

[147]

33

Vadimezan (Lung cancer)

In vivo: 15 Japanese patients with stage IV advanced non-small cell lung

cancer

In vivo: 600–1800 mg/m2

In vivo: paclitaxel (200 mg ⁄ m2) and carboplatin (at a plasma AUC of 6 mg ⁄ ml *

min)

In vivo: 6 cycle (Each treatment cycle span was

21 days)

Addition of ASA404 to the standard treatment (paclitaxel and carbopolatin) Decreased adverse effects

[149]

Vadimezan (Lung cancer)

In vivo: 108 squamous and non-squamous non-small cell

lung cancer patients

In vivo: 1200, 1800 mg/m2

paclitaxel (P; 175 mg/m2) and carboplatin (C; AUC 6 mg/ml•min)

In vivo: 6 cycle

Addition of ASA404 to the standard treatment (paclitaxel and carbopolatin) did not increase the toxicity and did not report a serious side effects

Addition of ASA404 to the standard treatment could improve the survival rate in both squamous and non-squamous population

[150]